Pauline Funchain

All Publications

• Retrospective analysis of immunotherapy outcomes in Black patients. The Lancet. Oncology Reynolds, K. L., Funchain, P. 2024

  View details for DOI 10.1016/S1470-2045(24)00586-2

  View details for PubMedID 39551066

• DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance. JCO precision oncology Conway, K., Edmiston, S. N., Vondras, A., Reiner, A., Corcoran, D. L., Shen, R., Parrish, E. A., Hao, H., Lin, L., Kenney, J. M., Ilelaboye, G., Kostrzewa, C. E., Kuan, P. F., Busam, K. J., Lezcano, C., Lee, T. K., Hernando, E., Googe, P. B., Ollila, D. W., Moschos, S., Gorlov, I., Amos, C. I., Ernstoff, M. S., Cust, A. E., Wilmott, J. S., Scolyer, R. A., Mann, G. J., Vergara, I. A., Ko, J., Rees, J. R., Yan, S., Nagore, E., Bosenberg, M., Rothberg, B. G., Osman, I., Lee, J. E., Saenger, Y., Bogner, P., Thompson, C. L., Gerstenblith, M., Holmen, S. L., Funchain, P., Brunsgaard, E., Depcik-Smith, N. D., Luo, L., Boyce, T., Orlow, I., Begg, C. B., Berwick, M., Thomas, N. E. 2024; 8: e2400375

  Abstract

  Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival.InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of melanoma recurrence or relapse. Methylation classes, distinguished by consensus clustering of 850K methylation data, were evaluated for their clinicopathologic characteristics, 5-year survival status, and differentially methylated gene sets.Among 422 InterMEL melanomas, consensus clustering revealed three primary melanoma methylation classes (MethylClasses): a CpG island methylator phenotype (CIMP) class, an intermediate methylation (IM) class, and a low methylation (LM) class. CIMP and IM were associated with higher AJCC stage (both P = .002), Breslow thickness (CIMP P = .002; IM P = .006), and mitotic index (both P < .001) compared with LM, while IM had higher N stage than CIMP (P = .01) and LM (P = .007). CIMP and IM had a 2-fold higher likelihood of 5-year death from melanoma than LM (CIMP odds ratio [OR], 2.16 [95% CI, 1.18 to 3.96]; IM OR, 2.00 [95% CI, 1.12 to 3.58]) in a multivariable model adjusted for age, sex, log Breslow thickness, ulceration, mitotic index, and N stage. Despite more extensive CpG island hypermethylation in CIMP, CIMP and IM shared similar patterns of differential methylation and gene set enrichment compared with LM.Melanoma MethylClasses may provide clinical value in predicting 5-year death from melanoma among patients with primary melanoma independent of other clinicopathologic factors.

  View details for DOI 10.1200/PO-24-00375

  View details for PubMedID 39509669

• Long-term cardiovascular outcomes of immune checkpoint inhibitor-related myocarditis: A large single-centre analysis. ESC heart failure Braghieri, L., Gharaibeh, A., Nkashama, L., Abushouk, A., Abushawer, O., Mehdizadeh-Shrifi, A., Honnekeri, B., Calabrese, C., Menon, V., Funchain, P., Collier, P., Sadler, D., Moudgil, R. 2024

  Abstract

  Immune checkpoint inhibitors (ICI) are the cornerstone of modern oncology; however, side effects such as ICI-related myocarditis (irM) can be fatal. Recently, Bonaca proposed criteria for irM; however, it is unknown if they correlate well with cardiovascular (CV) ICI-related adverse events. Additionally, whether incident irM portends worse long-term CV outcomes remains unclear. We aimed to determine the incidence of long-term CV comorbidities and CV mortality among irM patients.The ICI-related adverse event (irAE) registry was queried to identify irM patients by using Bonaca criteria. Random controls were selected after excluding patients with other concomitant irAEs. Patients' demographics, comorbidities and myocarditis presenting features were gathered. Outcomes included 2-year freedom from CV comorbidities (composite of atrial fibrillation, stroke, myocardial infarction and heart failure) and freedom from CV death. IrM was treated as a time-varying covariate.Seventy-six patients developed irM at a median of 167 days (mean age 69, 63.2% male, 47% lung cancer). Majority of patients had new wall motion abnormalities or EKG changes on presentation. Mean LVEF was 43%, median peak TnT was 0.81, and median NTproBNP was 2057 at irM onset. Two-year freedom from CV comorbidities (67% vs 86.8%, P < 0.001) and death (93.4% vs 99.3%, P = 0.003) was lower among irM patients. Incident irM was an independent predictor of CV death (HR 8.28, P = 0.048), but not CV comorbidities (HR 2.21, P = 0.080).This is the largest case-control study on irM highlighting worse long-term CV outcomes. Future studies are needed to establish appropriate therapeutic strategies and efficient screening strategies for irM survivors.

  View details for DOI 10.1002/ehf2.15131

  View details for PubMedID 39482568

• Real-world outcomes of patients with resected stage III melanoma treated with adjuvant therapies CANCER MEDICINE Dima, D., Lopetegui-Lia, N., Ogbue, O., Osantowski, B., Ullah, F., Jia, X., Song, J., Gastman, B., Isaacs, J., Kennedy, L., Funchain, P. 2024; 13 (12)

  View details for DOI 10.1002/cam4.7257

  View details for Web of Science ID 001251752600001

• TripleMoverlap syndrome (TMOS): Evaluating immune checkpoint inhibitor-related overlap syndrome of myocarditis, myositis and myasthenia gravis using an international pharmacovigilance database Naqash, A., Abushukair, H., Alghamdi, E., Laharwal, M., Gundroo, H. M., Tan, A., Funchain, P., Abdel-Wahab, N., Sharon, E., Johnson, D., Nassar, A., Al-Harbi, F. F. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557400585

• Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics. Journal for immunotherapy of cancer Phoon, Y. P., Lopes, J. E., Pfannenstiel, L. W., Marcela Diaz-Montero, C., Tian, Y. F., Ernstoff, M. S., Funchain, P., Ko, J. S., Winquist, R., Losey, H. C., Melenhorst, J. J., Gastman, B. R. 2024; 12 (4)

  Abstract

  Despite recent advances in immunotherapy, a substantial population of late-stage melanoma patients still fail to achieve sustained clinical benefit. Lack of translational preclinical models continues to be a major challenge in the field of immunotherapy; thus, more optimized translational models could strongly influence clinical trial development. To address this unmet need, we designed a preclinical model reflecting the heterogeneity in melanoma patients' clinical responses that can be used to evaluate novel immunotherapies and synergistic combinatorial treatment strategies. Using our all-autologous humanized melanoma mouse model, we examined the efficacy of a novel engineered interleukin 2 (IL-2)-based cytokine variant immunotherapy.To study immune responses and antitumor efficacy for human melanoma tumors, we developed an all-autologous humanized melanoma mouse model using clinically annotated, matched patient tumor cells and peripheral blood mononuclear cells (PBMCs). After inoculating immunodeficient NSG mice with patient tumors and an adoptive cell transfer of autologous PBMCs, mice were treated with anti-PD-1, a novel investigational engineered IL-2-based cytokine (nemvaleukin), or recombinant human IL-2 (rhIL-2). The pharmacodynamic effects and antitumor efficacy of these treatments were then evaluated. We used tumor cells and autologous PBMCs from patients with varying immunotherapy responses to both model the diversity of immunotherapy efficacy observed in the clinical setting and to recapitulate the heterogeneous nature of melanoma.Our model exhibited long-term survival of engrafted human PBMCs without developing graft-versus-host disease. Administration of an anti-PD-1 or nemvaleukin elicited antitumor responses in our model that were patient-specific and were found to parallel clinical responsiveness to checkpoint inhibitors. An evaluation of nemvaleukin-treated mice demonstrated increased tumor-infiltrating CD4+ and CD8+ T cells, preferential expansion of non-regulatory T cell subsets in the spleen, and significant delays in tumor growth compared with vehicle-treated controls or mice treated with rhIL-2.Our model reproduces differential effects of immunotherapy in melanoma patients, capturing the inherent heterogeneity in clinical responses. Taken together, these data demonstrate our model's translatability for novel immunotherapies in melanoma patients. The data are also supportive for the continued clinical investigation of nemvaleukin as a novel immunotherapeutic for the treatment of melanoma.

  View details for DOI 10.1136/jitc-2023-008066

  View details for PubMedID 38604813

• Germline Cancer Susceptibility in Individuals with Melanoma. Journal of the American Academy of Dermatology Funchain, P., Ni, Y., Heald, B., Bungo, B., Arbesman, M., Behera, T. R., McCormick, S., Song, J. M., Kennedy, L. B., Nielsen, S. M., Esplin, E. D., Nizialek, E., Ko, J., Diaz-Montero, C. M., Gastman, B., Stratigos, A. J., Artomov, M., Tsao, H., Arbesman, J. 2024

  Abstract

  BACKGROUND: Prior studies have estimated a small number of individuals with melanoma (2-2.5%) have germline cancer predisposition, yet a recent twin study suggested melanoma has the highest hereditability among cancers.OBJECTIVE: To determine the incidence of hereditary melanoma and characterize the spectrum of cancer predisposition genes that may increase the risk of melanoma.METHODS: 400 individuals with melanoma and personal or family history of cancers underwent germline testing of >80 cancer predisposition genes. Comparative analysis of germline data was performed on 3 additional oncologic and dermatologic datasets.RESULTS: Germline pathogenic/likely pathogenic (P/LP) variants were identified in 15.3% (61) individuals with melanoma. Most variants (41, 67%) involved genes considered unrelated to melanoma (BLM, BRIP1, CHEK2, MLH1, MSH2, PMS2, RAD51C). A third (20, 33%) were in genes previously associated with familial melanoma (BAP1, BRCA2, CDKN2A, MITF, TP53). Nearly half (30, 46.9%) of P/LP variants were in HRD genes. Validation cohorts demonstrated P/LP rates of 10.6% from an unselected oncologic cohort, 15.8% from a selected commercial testing cohort and 14.5% from a highly selected dermatologic study.LIMITATIONS: Cohorts with varying degrees of selection, some retrospective.CONCLUSION: Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.

  View details for DOI 10.1016/j.jaad.2023.11.070

  View details for PubMedID 38513832

• Toward the Development of Functional Biomarker Assays: Analysis of Neoadjuvant Intralesional Oncolytic Virus Response in High-Risk Stage II Melanoma Kirane, A., Lee, D., Ahmad, M., Sharma, S., Serasanambati, M., Lowe, M., Applebee, C., Safrygina, E., Swetter, S., Reddy, S., Warner, A., Funchain, P., Wang, J., Levy, R., Larijani, B., Maverakis, E. SPRINGER. 2024: S33-S34

  View details for Web of Science ID 001185577500066

• Clinical and Immunologic Features of Germline Pathogenic Variant (gPV) Positive Patients with Melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research Shen, A., Arbesman, M., Lodha, R., Rayman, P., Bungo, B., Ni, Y., Chan, T., Gastman, B., Ko, J., Diaz-Montero, C. M., Arbesman, J., Funchain, P. 2023

  Abstract

  Malignant melanoma represents the most lethal skin cancer with germline predispositions thought to comprise 10-15% of all melanoma cases. No studies to date examine the immunologic features that may differentiate survival differences between germline pathogenic variant (gPV) positive patients with melanoma from gPV negative patients with melanoma.Adult patients with melanoma and clinical characteristics suggesting hereditary predisposition to cancer were prospectively recruited to undergo germline testing and flow cytometric analysis of peripheral immune suppressor cells.In this cohort, gPV positive patients (n=72) had a significantly improved melanoma specific survival (MSS) compared to gPV negative patients (n=411) [HRadj = .32, 95% CI (.13 - .82), p = .01]. These survival improvements amongst gPV positive patients were most apparent amongst cutaneous melanoma subtypes [HRadj = .12, 95% CI (.016 - .86), p = .03] and numerically improved in later stage (IIB-IV) patients [HRadj = .34, 95% CI (.10 - 1.11), p = .06]. Further, gPV positive patients had a significantly lower level of total circulating PMN-MDSCs compared to gPV negative patients (p = .01), which was most apparent in those diagnosed with later stages (IIB-IV) of melanoma (p = .009). Finally, a significant upregulation of inflammatory transcriptome signatures in later stage gPV positive patients (n=21) was observed in comparison to gPV negative patients (n=173) in the cutaneous melanoma cohort (SKCM) of The Cancer Genome Atlas (TCGA).gPV positive patients with melanoma exhibit improved MSS in addition to reduced peripheral PMN-MDSCs and an enhanced inflammatory microenvironment.

  View details for DOI 10.1158/1078-0432.CCR-23-1964

  View details for PubMedID 38032355

• MC1R signaling through the cAMP-CREB/ATF-1 and ERK-NFκB pathways accelerates G1/S transition promoting breast cancer progression. NPJ precision oncology Chelakkot, V. S., Thomas, K., Romigh, T., Fong, A., Li, L., Ronen, S., Chen, S., Funchain, P., Ni, Y., Arbesman, J. 2023; 7 (1): 85

  Abstract

  MC1R, a G-protein coupled receptor, triggers ultraviolet light-induced melanin synthesis and DNA repair in melanocytes and is implicated in the pathogenesis of melanoma. Although widely expressed in different tissue types, its function in non-cutaneous tissue is relatively unknown. Herein, we demonstrate that disruptive MC1R variants associated with melanomagenesis are less frequently found in patients with several cancers. Further exploration revealed that breast cancer tissue shows a significantly higher MC1R expression than normal breast tissue, and knocking down MC1R significantly reduced cell proliferation in vitro and in vivo. Mechanistically, MC1R signaling through the MC1R-cAMP-CREB/ATF-1 and MC1R-ERK-NFκB axes accelerated the G1-S transition in breast cancer cells. Our results revealed a new association between MC1R and breast cancer, which could be potentially targeted therapeutically. Moreover, our results suggest that MC1R-enhancing/activating therapies should be used cautiously, as they might be pro-tumorigenic in certain contexts.

  View details for DOI 10.1038/s41698-023-00437-1

  View details for PubMedID 37679505

  View details for PubMedCentralID PMC10485002

• Systemic Therapy for Melanoma: ASCO Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Seth, R., Agarwala, S. S., Messersmith, H., Alluri, K. C., Ascierto, P. A., Atkins, M. B., Bollin, K., Chacon, M., Davis, N., Faries, M. B., Funchain, P., Gold, J. S., Guild, S., Gyorki, D. E., Kaur, V., Khushalani, N. I., Kirkwood, J. M., McQuade, J. L., Meyers, M. O., Provenzano, A., Robert, C., Santinami, M., Sehdev, A., Sondak, V. K., Spurrier, G., Swami, U., Truong, T. G., Tsai, K. K., van Akkooi, A., Weber, J. 2023: JCO2301136

  Abstract

  The ASCO Special Article by Seth et al entitled, "Systemic Therapy for Melanoma: ASCO Guideline Update," (J Clin Oncol 10.1200/JCO.23.01136) published in Journal of Clinical Oncology ahead of print on August 14, 2023, is under further review.Until the authors and their institutions can fully provide additional information, readers should interpret the findings presented with caution. An update will be provided when our investigation is complete.

  View details for DOI 10.1200/JCO.23.01136

  View details for PubMedID 37579248

• Characteristics of Immune Checkpoint Inhibitor-Associated Gastritis: Report from a Major Tertiary Care Center. The oncologist Farha, N., Faisal, M. S., Allende, D. S., Sleiman, J., Shah, R., Farha, N., Funchain, P., Philpott, J. R. 2023; 28 (8): 706-713

  Abstract

  Immune checkpoint inhibitors (ICIs) have increased our ability to treat an ever-expanding number of cancers. We describe a case series of 25 patients who were diagnosed with gastritis following ICI therapy.This was a retrospective study involving 1712 patients treated for malignancy with immunotherapy at Cleveland Clinic from January 2011 to June 2019 (IRB 18-1225). We searched electronic medical records using ICD-10 codes for gastritis diagnosis confirmed on endoscopy and histology within 3 months of ICI therapy. Patients with upper gastrointestinal tract malignancy or documented Helicobacter pylori-associated gastritis were excluded.Twenty-five patients were found to meet the criteria for diagnosis of gastritis. Of these 25 patients, most common malignancies were non-small cell lung cancer (52%) and melanoma (24%). Median number of infusions preceding symptoms was 4 (1-30) and time to symptom onset 2 (0.5-12) weeks after last infusion. Symptoms experienced were nausea (80%), vomiting (52%), abdominal pain (72%), and melena (44%). Common endoscopic findings were erythema (88%), edema (52%), and friability (48%). The most common diagnosis of pathology was chronic active gastritis in 24% of patients. Ninety-six percent received acid suppression treatment and 36% of patients also received steroids with an initial median dose of prednisone 75 (20-80) mg. Within 2 months, 64% had documented complete resolution of symptoms and 52% were able to resume immunotherapy.Patients presenting with nausea, vomiting, abdominal pain, or melena following immunotherapy should be assessed for gastritis and if other causes are excluded, may require treatment as consideration for complication of immunotherapy.

  View details for DOI 10.1093/oncolo/oyad031

  View details for PubMedID 36905577

  View details for PubMedCentralID PMC10400162

• Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium. Journal of clinical oncology : official journal of the American Society of Clinical Oncology El Zarif, T., Nassar, A. H., Adib, E., Fitzgerald, B. G., Huang, J., Mouhieddine, T. H., Rubinstein, P. G., Nonato, T., McKay, R. R., Li, M., Mittra, A., Owen, D. H., Baiocchi, R. A., Lorentsen, M., Dittus, C., Dizman, N., Falohun, A., Abdel-Wahab, N., Diab, A., Bankapur, A., Reed, A., Kim, C., Arora, A., Shah, N. J., El-Am, E., Kozaily, E., Abdallah, W., Al-Hader, A., Abu Ghazal, B., Saeed, A., Drolen, C., Lechner, M. G., Drakaki, A., Baena, J., Nebhan, C. A., Haykal, T., Morse, M. A., Cortellini, A., Pinato, D. J., Dalla Pria, A., Hall, E., Bakalov, V., Bahary, N., Rajkumar, A., Mangla, A., Shah, V., Singh, P., Aboubakar Nana, F., Lopetegui-Lia, N., Dima, D., Dobbs, R. W., Funchain, P., Saleem, R., Woodford, R., Long, G. V., Menzies, A. M., Genova, C., Barletta, G., Puri, S., Florou, V., Idossa, D., Saponara, M., Queirolo, P., Lamberti, G., Addeo, A., Bersanelli, M., Freeman, D., Xie, W., Reid, E. G., Chiao, E. Y., Sharon, E., Johnson, D. B., Ramaswami, R., Bower, M., Emu, B., Marron, T. U., Choueiri, T. K., Baden, L. R., Lurain, K., Sonpavde, G. P., Naqash, A. R. 2023; 41 (21): 3712-3723

  Abstract

  Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer.This retrospective study included PWH treated with anti-PD-1- or anti-PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC).Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti-PD-1/anti-PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was -0.06 months (95% CI, -5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, -4.02 to 8.48; P = .48) for OS.Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

  View details for DOI 10.1200/JCO.22.02459

  View details for PubMedID 37192435

  View details for PubMedCentralID PMC10351941

• Role of C-Reactive Protein in Predicting the Severity and Response of Immune-Mediated Diarrhea and Colitis in Patients with Cancer. Journal of Cancer Liu, C., Shatila, M., Mathew, A., Machado, A. P., Thomas, A., Zhang, H. C., Thomas, A. S., Faleck, D., Funchain, P., Philpott, J., Grivas, P., Obeid, M., Carbonnel, F., Wang, Y. 2023; 14 (10): 1913-1919

  Abstract

  Background: Immune-mediated diarrhea and colitis (IMDC) frequently develop after treatment with immune checkpoint inhibitors. C-reactive protein (CRP) is a serum inflammatory biomarker used to stratify and monitor disease severity in many inflammatory conditions. However, CRP level is not specific and is widely influenced by various factors non-specific to bowel inflammation. We aimed to study the utility of CRP as a predictor of disease severity and therapy response in IMDC. Methods: We performed a retrospective analysis of patients diagnosed with IMDC who had CRP measured at IMDC onset and after treatment with selective immunosuppressive therapy (SIT: infliximab and vedolizumab), between 01/2016 and 02/2022 at MD Anderson Cancer Center. Patient demographics, clinical characteristics, and IMDC data were collected and analyzed. Results: Our sample of 128 patients had a median age of 67 years; most were white (89.8%); and male (65.6%). Prior to development of IMDC, 15 (11.7%) were initially treated with anti-CTLA-4, 42 (32.8%) with anti-PD-1 or PD-L1, and 71 (55.5%) with a combination of both. We found higher CRP level was associated with higher CTCAE grade of clinical symptoms such as diarrhea (p=0.015), colitis (p=0.013), and endoscopic findings (p=0.016). While CRP levels decreased after IMDC treatment, there was no significant association between CRP levels with clinical remission, endoscopic remission or histologic remission. There also was no significant correlation between CRP level and recurrence of IMDC, or with fecal calprotectin levels. Conclusion: CRP level may be useful to assess initial severity of IMDC, including grade of diarrhea and colitis and degree of endoscopic inflammation. However, CRP is not a robust surrogate biomarker for assessing treatment response or disease recurrence. Despite the reduction of CRP levels observed following IMDC treatment, this finding might be nonspecific and potentially confounded by concurrent clinical factors, such as underlying malignancy, other inflammatory processes, and systemic anti-cancer therapy. Further studies of the role of CRP are warranted in patients with cancer and IMDC.

  View details for DOI 10.7150/jca.84261

  View details for PubMedID 37476185

  View details for PubMedCentralID PMC10355204

• Predictors for the development of neurological immune-related adverse events of immune checkpoint inhibitors and impact on mortality. European journal of neurology Yan, C., Huang, M., Swetlik, C., Toljan, K., Mahadeen, A. Z., Bena, J., Kunchok, A., Funchain, P., McGinley, M. 2023

  Abstract

  Little is known about risk factors for developing neurological immunological adverse events (neuro-irAEs) from immune checkpoint inhibitors (ICIs). We report the incidence, predictors for development, impact on mortality of neuro-irAEs, and impact of ICIs on pre-existing neurological conditions in a large clinical cohort.Patients who received ICIs between January 2011 and December 2018 were identified from a tertiary cancer center registry. Descriptive statistics were used to summarize patient, cancer, and treatment data. Odds ratios from univariable and multivariable logistic regression models were calculated to identify potential predictors for developing a neuro-irAE. Impact of neuro-irAEs on overall survival was estimated by Kaplan-Meier and Cox proportional hazard models.Overall frequency of neurological irAEs was 2.3%. Peripheral nervous system complications were most frequent (53.6%). Melanoma, younger age, prior chemotherapy, prior resection, CTLA-4 ICIs exposure, and combination PD-1 and CTLA-4 ICIs exposure had significantly higher odds for developing a neuro-irAE (p < 0.05) in univariate but not multivariate models. Those with a neuro-irAE were less likely to die at 3 years compared to those without a neuro-irAE (69% vs. 55%, p = 0.004) in univariate but not multivariate model. Flare of pre-existing neurological condition after exposure to ICIs was present (15.4%, 2 of 13 patients) but manageable. One patient was rechallenged with ICIs without recurrent flare.Neuro-irAEs are not associated with increase in overall mortality. Potential predictors for the development of neuro-irAEs are younger age, melanoma, prior chemotherapy and resection, CTLA-4, or combination ICIs exposure.

  View details for DOI 10.1111/ene.15942

  View details for PubMedID 37350150

• Melanoma body site distribution: Germline genetics may have a lesser role. JAAD international Decosma, L., Ni, Y., Funchain, P., Arbesman, J. 2023; 11: 220-221

  View details for DOI 10.1016/j.jdin.2023.03.003

  View details for PubMedID 37152215

  View details for PubMedCentralID PMC10154950

• Reincarnating autoimmunity: Immune-related adverse events as new diseases. Cleveland Clinic journal of medicine Funchain, P. 2023; 90 (5): 318-319

  View details for DOI 10.3949/ccjm.90a.23013

  View details for PubMedID 37127333

• InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma. PloS one Orlow, I., Sadeghi, K. D., Edmiston, S. N., Kenney, J. M., Lezcano, C., Wilmott, J. S., Cust, A. E., Scolyer, R. A., Mann, G. J., Lee, T. K., Burke, H., Jakrot, V., Shang, P., Ferguson, P. M., Boyce, T. W., Ko, J. S., Ngo, P., Funchain, P., Rees, J. R., O'Connell, K., Hao, H., Parrish, E., Conway, K., Googe, P. B., Ollila, D. W., Moschos, S. J., Hernando, E., Hanniford, D., Argibay, D., Amos, C. I., Lee, J. E., Osman, I., Luo, L., Kuan, P. F., Aurora, A., Gould Rothberg, B. E., Bosenberg, M. W., Gerstenblith, M. R., Thompson, C., Bogner, P. N., Gorlov, I. P., Holmen, S. L., Brunsgaard, E. K., Saenger, Y. M., Shen, R., Seshan, V., Nagore, E., Ernstoff, M. S., Busam, K. J., Begg, C. B., Thomas, N. E., Berwick, M. 2023; 18 (4): e0269324

  Abstract

  We are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients. We also evaluated tissue-derived predictors of extracted nucleic acids' quality and success in downstream testing. This ongoing study will target 1,000 melanomas within the international InterMEL consortium.Following a pre-established protocol, participating centers ship formalin-fixed paraffin embedded (FFPE) tissue sections to Memorial Sloan Kettering Cancer Center for the centralized handling, dermatopathology review and histology-guided coextraction of RNA and DNA. Samples are distributed for evaluation of somatic mutations using next gen sequencing (NGS) with the MSK-IMPACTTM assay, methylation-profiling (Infinium MethylationEPIC arrays), and miRNA expression (Nanostring nCounter Human v3 miRNA Expression Assay).Sufficient material was obtained for screening of miRNA expression in 683/685 (99%) eligible melanomas, methylation in 467 (68%), and somatic mutations in 560 (82%). In 446/685 (65%) cases, aliquots of RNA/DNA were sufficient for testing with all three platforms. Among samples evaluated by the time of this analysis, the mean NGS coverage was 249x, 59 (18.6%) samples had coverage below 100x, and 41/414 (10%) failed methylation QC due to low intensity probes or insufficient Meta-Mixed Interquartile (BMIQ)- and single sample (ss)- Noob normalizations. Six of 683 RNAs (1%) failed Nanostring QC due to the low proportion of probes above the minimum threshold. Age of the FFPE tissue blocks (p<0.001) and time elapsed from sectioning to co-extraction (p = 0.002) were associated with methylation screening failures. Melanin reduced the ability to amplify fragments of 200bp or greater (absent/lightly pigmented vs heavily pigmented, p<0.003). Conversely, heavily pigmented tumors rendered greater amounts of RNA (p<0.001), and of RNA above 200 nucleotides (p<0.001).Our experience with many archival tissues demonstrates that with careful management of tissue processing and quality control it is possible to conduct multi-omic studies in a complex multi-institutional setting for investigations involving minute quantities of FFPE tumors, as in studies of early-stage melanoma. The study describes, for the first time, the optimal strategy for obtaining archival and limited tumor tissue, the characteristics of the nucleic acids co-extracted from a unique cell lysate, and success rate in downstream applications. In addition, our findings provide an estimate of the anticipated attrition that will guide other large multicenter research and consortia.

  View details for DOI 10.1371/journal.pone.0269324

  View details for PubMedID 37011054

  View details for PubMedCentralID PMC10069769

• Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma: A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial. JAMA oncology Unger, J. M., Darke, A., Othus, M., Truong, T. G., Khushalani, N., Kendra, K., Lewis, K. D., Faller, B., Funchain, P., Buchbinder, E. I., Tarhini, A. A., Kirkwood, J. M., Sharon, E., Sondak, V., Guild, S. R., Grossmann, K., Ribas, A., Patel, S. P. 2023; 9 (2): 251-260

  Abstract

  A key issue for the adjuvant treatment of patients with melanoma is the assessment of the effect of treatment on relapse, survival, and quality of life (QOL).To compare QOL in patients with resected melanoma at high risk for relapse who were treated with adjuvant pembrolizumab vs standard of care with either ipilimumab or high-dose interferon α 2b (HDI).The S1404 phase 3 randomized clinical trial was conducted by the SWOG Cancer Research Network at 211 community/academic sites in the US, Canada, and Ireland. Patients were enrolled from December 2015 to October 2017. Data analysis for this QOL substudy was completed in March 2022. Overall, 832 patients were evaluable for the primary QOL end point.Patients were randomized (1:1) to treatment with adjuvant pembrolizumab vs standard of care with ipilimumab/HDI.Quality of life was assessed for patients at baseline and cycles 1, 3, 5, 7, and 9 after randomization using the Functional Assessment of Cancer Therapy (FACT) Biological Response Modifiers (FACT-BRM), FACT-General, Functional Assessment of Chronic Illness Therapy-Diarrhea, and European QOL 5-Dimension 3-Level scales. The primary end point was the comparison by arm of cycle 3 FACT-BRM trial outcome index (TOI) scores using linear regression. Linear-mixed models were used to evaluate QOL scores over time. Regression analyses included adjustments for the baseline score, disease stage, and programmed cell death ligand 1 status. A clinically meaningful difference of 5 points was targeted.Among 1303 eligible patients (median [range] age, 56.7 [18.3-86.0] years; 524 women [40.2%]; 779 men [59.8%]; 10 Asian [0.8%], 7 Black [0.5%], 44 Hispanic [3.4%], and 1243 White [95.4%] individuals), 1188 (91.1%) had baseline FACT-BRM TOI scores, and 832 were evaluable at cycle 3 (ipilimumab/HDI = 267 [32.1%]; pembrolizumab = 565 [67.9%]). Evaluable patients were predominantly younger than 65 years (623 [74.9%]) and male (779 [58.9%]). Estimates of FACT-BRM TOI cycle 3 compliance did not differ by arm (ipilimumab/HDI, 96.0% vs pembrolizumab, 98.3%; P = .25). The adjusted cycle 3 FACT-BRM TOI score was 9.6 points (95% CI, 7.9-11.3; P < .001) higher (better QOL) for pembrolizumab compared with ipilimumab/HDI, exceeding the prespecified clinically meaningful difference. In linear-mixed models, differences by arm exceeded 5 points in favor of pembrolizumab through cycle 7. In post hoc analyses, FACT-BRM TOI scores favored the pembrolizumab arm compared with the subset of patients receiving ipilimumab (difference, 6.0 points; 95% CI, 4.1-7.8; P < .001) or HDI (difference, 17.0 points; 95% CI, 14.6-19.4; P < .001).This secondary analysis of a phase 3 randomized clinical trial found that adjuvant pembrolizumab improved QOL vs treatment with adjuvant ipilimumab or HDI in patients with high-risk resected melanoma.ClinicalTrials.gov identifier: NCT02506153.

  View details for DOI 10.1001/jamaoncol.2022.5486

  View details for PubMedID 36416836

  View details for PubMedCentralID PMC9685550

• Immune checkpoint inhibitor induced myocarditis, myasthenia gravis, and myositis: A single-center case series. Cancer medicine Longinow, J., Zmaili, M., Skoza, W., Kondoleon, N., Marquardt, R., Calabrese, C., Funchain, P., Moudgil, R. 2023; 12 (3): 2281-2289

  Abstract

  Immune checkpoint inhibitors can result in overlap syndrome comprised of myasthenia gravis, myositis and myocarditis. However, the mortality predictors have not been clearly delineated.We examined the characteristics of 11 patients diagnosed with overlap syndrome at Cleveland Clinic. All the available clinical, diagnostic, biochemical and disease specific factors were examined. Clinical predictors of increased mortality were using student t-test for parametric data and Wilcoxon-signed rank testing for nonparametric data.Seven patients out of eleven patients were alive during the analysis. Our study did confirm that troponins were indicator of early demise. However, study showed that elevated creatinine, BUN, and decreased hemoglobin were also observed in patients who met early demise. Unlike previously published studies, elevated NT Pro-BNP and reduced left ventricular ejection fraction were not a seen in this study. However, there were higher incidence of electrical abnormalities in deceased patients when compared to alive.Our study is first to examine various clinical parameters of overlap syndrome that might be predictive of mortality. This study confirms troponin as possible predictor and adds elevated creatinine, BUN and reduced hemoglobin as possible early biomarkers in deceased patients. The analysis showed that reduced LVEF was not a seen in deceased patients.

  View details for DOI 10.1002/cam4.5050

  View details for PubMedID 36128926

  View details for PubMedCentralID PMC9939107

• Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Atkins, M. B., Lee, S. J., Chmielowski, B., Tarhini, A. A., Cohen, G. I., Truong, T. G., Moon, H. H., Davar, D., O'Rourke, M., Stephenson, J. J., Curti, B. D., Urba, W. J., Brell, J. M., Funchain, P., Kendra, K. L., Ikeguchi, A. P., Jaslowski, A., Bane, C. L., Taylor, M. A., Bajaj, M., Conry, R. M., Ellis, R. J., Logan, T. F., Laudi, N., Sosman, J. A., Crockett, D. G., Pecora, A. L., Okazaki, I. J., Reganti, S., Chandra, S., Guild, S., Chen, H. X., Streicher, H. Z., Wolchok, J. D., Ribas, A., Kirkwood, J. M. 2023; 41 (2): 186-197

  Abstract

  Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4-blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy.In a phase III trial, patients with treatment-naive BRAFV600-mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety.A total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A (P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B (P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated.Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

  View details for DOI 10.1200/JCO.22.01763

  View details for PubMedID 36166727

  View details for PubMedCentralID PMC9839305

• Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study. Pigment cell & melanoma research Luo, L., Shen, R., Arora, A., Orlow, I., Busam, K. J., Lezcano, C., Lee, T. K., Hernando, E., Gorlov, I., Amos, C., Ernstoff, M. S., Seshan, V. E., Cust, A. E., Wilmott, J., Scolyer, R. A., Mann, G., Nagore, E., Funchain, P., Ko, J., Ngo, P., Edmiston, S. N., Conway, K., Googe, P. B., Ollila, D., Lee, J. E., Fang, S., Rees, J. R., Thompson, C. L., Gerstenblith, M., Bosenberg, M., Gould Rothberg, B., Osman, I., Saenger, Y., Reynolds, A. Z., Schwartz, M., Boyce, T., Holmen, S., Brunsgaard, E., Bogner, P., Kuan, P. F., Wiggins, C., Thomas, N. E., Begg, C. B., Berwick, M. 2022; 35 (6): 605-612

  Abstract

  It is unclear why some melanomas aggressively metastasize while others remain indolent. Available studies employing multi-omic profiling of melanomas are based on large primary or metastatic tumors. We examine the genomic landscape of early-stage melanomas diagnosed prior to the modern era of immunological treatments. Untreated cases with Stage II/III cutaneous melanoma were identified from institutions throughout the United States, Australia and Spain. FFPE tumor sections were profiled for mutation, methylation and microRNAs. Preliminary results from mutation profiling and clinical pathologic correlates show the distribution of four driver mutation sub-types: 31% BRAF; 18% NRAS; 21% NF1; 26% Triple Wild Type. BRAF mutant tumors had younger age at diagnosis, more associated nevi, more tumor infiltrating lymphocytes, and fewer thick tumors although at generally more advanced stage. NF1 mutant tumors were frequent on the head/neck in older patients with severe solar elastosis, thicker tumors but in earlier stages. Triple Wild Type tumors were predominantly male, frequently on the leg, with more perineural invasion. Mutations in TERT, TP53, CDKN2A and ARID2 were observed often, with TP53 mutations occurring particularly frequently in the NF1 sub-type. The InterMEL study will provide the most extensive multi-omic profiling of early-stage melanoma to date. Initial results demonstrate a nuanced understanding of the mutational and clinicopathological landscape of these early-stage tumors.

  View details for DOI 10.1111/pcmr.13058

  View details for PubMedID 35876628

  View details for PubMedCentralID PMC9640183

• A phase II study of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations. Future oncology (London, England) Rodón, J., Funchain, P., Laetsch, T. W., Arkenau, H. T., Hervieu, A., Singer, C. F., Murciano-Goroff, Y. R., Chawla, S. P., Anthony, K., Yamamiya, I., Liu, M., Halim, A. B., Benhadji, K. A., Takahashi, O., Delaloge, S. 2022; 18 (30): 3377-3387

  Abstract

  PTEN acts as a potent tumor suppressor within the PI3K/AKT/mTOR pathway. Germline mutations in the PTEN gene are a hallmark of PTEN hamartoma tumor syndrome, which includes Cowden syndrome, where they appear to elevate lifetime risk of cancer. Targeted AKT directed therapy has been proposed as an effective approach in cancer patients having germline PTEN mutations. The mechanism of action, safety and dosing regimen for the novel allosteric AKT inhibitor TAS-117 have been explored in a phase I study in Japan in which activity was observed against certain tumor types. Here we describe the study protocol of an international, two-part phase II study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations.

  View details for DOI 10.2217/fon-2022-0305

  View details for PubMedID 36039910

  View details for PubMedCentralID PMC10334253

• Thromboembolism in Patients with Metastatic Urothelial Cancer Treated with Immune Checkpoint Inhibitors. Targeted oncology Sheng, I. Y., Gupta, S., Reddy, C. A., Angelini, D., Funchain, P., Sussman, T. A., Sleiman, J., Ornstein, M. C., McCrae, K., Khorana, A. A. 2022; 17 (5): 563-569

  Abstract

  Immunotherapy has become one of the mainstays for metastatic urothelial carcinoma treatment. Whether immune checkpoint inhibitor therapy increases thromboembolism (TE) risk is unknown.We investigated the incidence of arterial thromboembolism (ATE) and venous thromboembolism (VTE) events and its associated outcomes in patients with metastatic urothelial cancer treated with immune checkpoint inhibitors.Patients with urothelial cancer treated with immune checkpoint inhibitors at the Cleveland Clinic from 1/1/2015 to 12/31/2019 were identified. The Kaplan-Meier method estimated overall survival and Cox proportional hazards regression evaluated the impact of TE on overall survival.Of 279 patients, 72% were men with pure urothelial cancer (62%) who started atezolizumab (40%), nivolumab (3%), or pembrolizumab (57%). At a median follow-up of 5.6 months (range 0.3-51.6), 42 patients developed a TE (VTE n = 37, 13%, ATE n = 5, 2%). The cumulative incidence of TE after immune checkpoint inhibitor therapy was 9.1% (95% confidence interval 6.0-13.0) at 6 months and 13.6% (95% confidence interval 9.6-18.4) at 12 months. Most TE (VTE 62%, ATE 100%) occurred within 6 months of immune checkpoint inhibitor initiation (median doses 5, range 1-59), and the majority (VTE 81%, ATE 100%) resulted in hospitalization (median: 5 days, 4 days, respectively). Thromboembolism (hazard ratio 2.296, p = 0.0004), Bajorin score 1 or 2 (hazard ratio 1.490, p = 0.0315), and Bajorin score 2 (hazard ratio 3.50, p < 0.0001) were associated with worse overall survival.Immune checkpoint inhibitors are associated with a high TE risk. Thromboembolism is associated with worsened survival, among other poor outcomes. Further investigation into the mechanism behind immune checkpoint inhibitor-associated TE is needed.

  View details for DOI 10.1007/s11523-022-00905-x

  View details for PubMedID 35986816

• Outcomes of stage IV melanoma in the era of immunotherapy: a National Cancer Database (NCDB) analysis from 2014 to 2016. Journal for immunotherapy of cancer Sussman, T. A., Knackstedt, R., Wei, W., Funchain, P., Gastman, B. R. 2022; 10 (8)

  Abstract

  To evaluate factors affecting the utilization of immunotherapy and to stratify results based on the approval of ipilimumab in 2011 and programmed death-1 inhibitors in 2014, an analysis of available data from the National Cancer Database (NCDB) was performed.The NCDB was analyzed to identify patients with stage IV melanoma from 2004 to 2016. Patients were categorized during the time periods 2004-2010, 2011-2014, and 2015-2016. Overall survival (OS) was analyzed by Kaplan-Meier, log-rank, and Cox proportional hazard models; IO status was analyzed using logistic regression.24,544 patients were analyzed. Overall, 5238 patients (21.3%) who received IO had improved median OS compared with those who did not (20.2 months vs 7.4 months; p<0.0001). Between 2004 and 2010, 9.7% received immunotherapy; from 2011 to 2014, 21.9% received immunotherapy; and from 2015 to 2016, 43.5% received immunotherapy. Three-year OS significantly improved in patients treated with IO across treatment years: 31% (95% CI 29% to 34%) from 2004 to 2010, 35% (95% CI 33% to 37%) from 2011 to 2014, and 46% (95% CI 44% to 48%) from 2015 to 2016 (p<0.0001). Survival was worse in patients who did not receive IO during these treatment years: 16% (15%-17%), 21% (20%-22%), and 27% (25%-28%), respectively. In the overall cohort, age <65 years, female gender, private insurance, no comorbidities, residence in metropolitan area, and treatment at academic centers were associated with better OS (p<0.0001 for all). In the multivariate analysis, receipt of IO from 2015 to 2016 was associated with age <65 years (OR 1.27, 95% CI 1.08 to 1.50), African American race (OR 5.88, 95% CI 1.60 to 28.58), lack of comorbidities (OR 1.43, 95% CI 1.23 to 1.66), and treatment at academic centers (OR 1.44, 95% CI 1.26 to 1.65) (p<0.05 for all).OS improved in patients with stage IV melanoma receiving IO, with the highest OS rate in 2015-2016. Our findings, which represent a real-world population, are slightly lower than recent trials, such as KEYNOTE-006 and CheckMate 067. Significant socioeconomic factors may impact receipt of IO and survival.

  View details for DOI 10.1136/jitc-2022-004994

  View details for PubMedID 35998982

  View details for PubMedCentralID PMC9403163

• Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Seth, R., Messersmith, H., Funchain, P. 2022; 40 (21): 2375-2377

  Abstract

  ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options.

  View details for DOI 10.1200/JCO.22.00944

  View details for PubMedID 35658488

• ss-2 adrenergic receptor (AR): Another immune checkpoint (IC)" A phase II clinical trial of propranolol (P) with pembrolizumab (Pem) in patients with unresectable stage III and stage IV melanoma Switzer, B., Pandey, M. R., Valentine, A., Witkiewicz, A., Knudsen, E., Attwood, K., Tario, J., Funchain, P., Drabick, J. J., Mohammadpour, H., Ernstoff, M. S., Puzanov, I., Repasky, E. A., Gandhi, S. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509500072

• Circulating Tumor DNA Testing Supports Rapid Therapeutic Decision-Making in Metastatic Melanoma: A Case Report. Frontiers in oncology Behera, T. R., Song, J. M., Ko, J., Eicher, D., Arbesman, J., Gastman, B., Farkas, D. H., Funchain, P. 2022; 12: 846187

  Abstract

  Treatment of metastatic melanoma includes the option of targeted therapy in patients with driver BRAF mutations. BRAF-MEK inhibitor drugs improve survival in the approximately 50% of patients with melanoma that harbor BRAF mutations. As BRAF mutation detection in tissue often takes days to weeks, it is not always possible or timely to obtain BRAF status in tissue using immunohistochemistry or next generation sequencing. Plasma-derived circulating tumor DNA (ctDNA) is a potential alternative analyte in such treatment settings. We present a case of metastatic melanoma that was treated in an emergent setting using therapy supported by rapid PCR-based detection of ctDNA positive for a BRAF V600 mutation. In this rapidly deteriorating 53-year-old male with diffuse melanoma metastases and unknown BRAF mutation status requiring hospital admission, a plasma-based BRAF mutation detection supported treatment with targeted therapy, dabrafenib and trametinib. Same-day initiation of therapy resulted in swift amelioration allowing discharge within a week, followed by substantial clinical improvement over the following weeks. In cases requiring urgent clinical decision making, a plasma-based, near point-of-care detection system is useful in supporting targeted therapy decisions without the need for invasive and time-consuming biopsy.

  View details for DOI 10.3389/fonc.2022.846187

  View details for PubMedID 35756682

  View details for PubMedCentralID PMC9231430

• Germline predisposition in oncologic and dermatologic melanoma cohorts. Funchain, P., Ni, Y., Bungo, B., Heald, B., Arbesman, M., Behera, T., Nielsen, S. M., McCormick, S., Song, J., Nizialek, E., Gastman, B., Esplin, E. D., Artomov, M., Tsao, H., Arbesman, J. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680300136

• Gastrointestinal Toxicities of Immune Checkpoint Inhibitors Are Associated With Enhanced Tumor Responsiveness and Improved Survival. Gastroenterology research Alomari, M., Al Ashi, S., Chadalavada, P., Khazaaleh, S., Covut, F., Al Momani, L., Elkafrawy, A., Padbidri, V., Funchain, P., Campbell, D., Romero-Marrero, C. 2022; 15 (2): 56-66

  Abstract

  Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced malignancies. However, they are associated with the development of multiple gastrointestinal immune-related adverse events (GI-irAEs). We aimed to evaluate the types and severity of GI-irAEs associated with ICI therapy, to identify potential risk factors for developing GI-irAEs and to determine the relationship of GI-irAEs development to tumor responsiveness and overall survival.All patients who received ICIs for advanced malignancies at our center were included. Medical records were reviewed, and data extraction included: baseline demographic characteristics, immunotherapy regimens, development of GI-irAEs, response to treatment, and overall survival. Overall survival was calculated from the date of treatment initiation and estimated by the Kaplan-Meier method.Five hundred sixty-seven patients received ICI therapy for stage IV malignancies. Forty-one (7%) patients experienced at least one GI-irAE. Among those experiencing GI-irAEs, 23 (56%) developed hepatitis, 17 (42%) developed colitis, four (10%) developed pancreatitis, and two (5%) developed gastritis. Patients who developed GI-irAEs experienced a better response to ICI therapy compared to patients who did not develop GI-irAEs (41% vs. 27%, P = 0.003). The 2-year overall survival rate of stage IV cancer patients who developed GI-irAEs was 62% (95% confidence interval (CI): 49 - 79) and 36% for those who did not develop GI-irAEs (95% CI: 32 - 41) (P = 0.002). The median follow-up time of surviving patients was 28 months. Twelve (29%) of the patients receiving dual ICI therapy developed GI-irAEs.Hepatitis, colitis, and pancreatitis were the most commonly encountered GI-irAEs with ICI therapy. Development of these GI-irAEs was associated with superior tumor responsiveness and better overall survival.

  View details for DOI 10.14740/gr1491

  View details for PubMedID 35572476

  View details for PubMedCentralID PMC9076156

• Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. Cancer discovery Grossmann, K. F., Othus, M., Patel, S. P., Tarhini, A. A., Sondak, V. K., Knopp, M. V., Petrella, T. M., Truong, T. G., Khushalani, N. I., Cohen, J. V., Buchbinder, E. I., Kendra, K., Funchain, P., Lewis, K. D., Conry, R. M., Chmielowski, B., Kudchadkar, R. R., Johnson, D. B., Li, H., Moon, J., Eroglu, Z., Gastman, B., Kovacsovics-Bankowski, M., Gunturu, K. S., Ebbinghaus, S. W., Ahsan, S., Ibrahim, N., Sharon, E., Korde, L. A., Kirkwood, J. M., Ribas, A. 2022; 12 (3): 644-653

  Abstract

  We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59-0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61-1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma.Adjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587.

  View details for DOI 10.1158/2159-8290.CD-21-1141

  View details for PubMedID 34764195

  View details for PubMedCentralID PMC8904282

• A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients. The Journal of experimental medicine Li, C., Phoon, Y. P., Karlinsey, K., Tian, Y. F., Thapaliya, S., Thongkum, A., Qu, L., Matz, A. J., Cameron, M., Cameron, C., Menoret, A., Funchain, P., Song, J. M., Diaz-Montero, C. M., Tamilselvan, B., Golden, J. B., Cartwright, M., Rodriguez, A., Bonin, C., Vella, A., Zhou, B., Gastman, B. R. 2022; 219 (1)

  Abstract

  Immune checkpoint inhibitor (ICI) therapy continues to revolutionize melanoma treatment, but only a subset of patients respond. Major efforts are underway to develop minimally invasive predictive assays of ICI response. Using single-cell transcriptomics, we discovered a unique CD8 T cell blood/tumor-shared subpopulation in melanoma patients with high levels of oxidative phosphorylation (OXPHOS), the ectonucleotidases CD38 and CD39, and both exhaustion and cytotoxicity markers. We called this population with high levels of OXPHOS "CD8+ TOXPHOS cells." We validated that higher levels of OXPHOS in tumor- and peripheral blood-derived CD8+ TOXPHOS cells correlated with ICI resistance in melanoma patients. We then developed an ICI therapy response predictive model using a transcriptomic profile of CD8+ TOXPHOS cells. This model is capable of discerning responders from nonresponders using either tumor or peripheral blood CD8 T cells with high accuracy in multiple validation cohorts. In sum, CD8+ TOXPHOS cells represent a critical immune population to assess ICI response with the potential to be a new target to improve outcomes in melanoma patients.

  View details for DOI 10.1084/jem.20202084

  View details for PubMedID 34807232

  View details for PubMedCentralID PMC8611729

• Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Schneider, B. J., Naidoo, J., Santomasso, B. D., Lacchetti, C., Adkins, S., Anadkat, M., Atkins, M. B., Brassil, K. J., Caterino, J. M., Chau, I., Davies, M. J., Ernstoff, M. S., Fecher, L., Ghosh, M., Jaiyesimi, I., Mammen, J. S., Naing, A., Nastoupil, L. J., Phillips, T., Porter, L. D., Reichner, C. A., Seigel, C., Song, J. M., Spira, A., Suarez-Almazor, M., Swami, U., Thompson, J. A., Vikas, P., Wang, Y., Weber, J. S., Funchain, P., Bollin, K. 2021; 39 (36): 4073-4126

  Abstract

  To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy.A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 through 2021.A total of 175 studies met the eligibility criteria of the systematic review and were pertinent to the development of the recommendations. Because of the paucity of high-quality evidence, recommendations are based on expert consensus.Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to the organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert ≤ grade 1. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines.

  View details for DOI 10.1200/JCO.21.01440

  View details for PubMedID 34724392

• Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Santomasso, B. D., Nastoupil, L. J., Adkins, S., Lacchetti, C., Schneider, B. J., Anadkat, M., Atkins, M. B., Brassil, K. J., Caterino, J. M., Chau, I., Davies, M. J., Ernstoff, M. S., Fecher, L., Funchain, P., Jaiyesimi, I., Mammen, J. S., Naidoo, J., Naing, A., Phillips, T., Porter, L. D., Reichner, C. A., Seigel, C., Song, J. M., Spira, A., Suarez-Almazor, M., Swami, U., Thompson, J. A., Vikas, P., Wang, Y., Weber, J. S., Bollin, K., Ghosh, M. 2021; 39 (35): 3978-3992

  Abstract

  To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell therapy.A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021.The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus.The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell-related toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell-associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell-associated neurotoxicity syndrome should be managed with corticosteroids and supportive care.Additional information is available at www.asco.org/supportive-care-guidelines.

  View details for DOI 10.1200/JCO.21.01992

  View details for PubMedID 34724386

• Thromboembolism in Patients with Metastatic Renal Cell Carcinoma Treated with Immunotherapy. Targeted oncology Sheng, I. Y., Gupta, S., Reddy, C. A., Angelini, D., Funchain, P., Sussman, T. A., Sleiman, J., Ornstein, M. C., McCrae, K., Khorana, A. A. 2021; 16 (6): 813-821

  Abstract

  Metastatic renal cell carcinoma (mRCC) is associated with a high risk of thromboembolism (TE).We investigated whether immunotherapy (IO) increases the hypercoagulable state in this high-risk population.Patients with mRCC treated with IO between 1 January 2015 and 31 December 2019 at the Cleveland Clinic were identified. Cumulative incidence analysis calculated TE rates over time and Gray's test determined differences in TE rates among groups. The Kaplan-Meier method estimated survival, while Cox proportional hazard regression evaluated the impact of TE on OS.Of 351 patients, 75% were men with clear cell mRCC (81%) and International Metastatic Renal Cell Carcinoma (IMDC) intermediate- to poor-risk disease (77%). Patients received single-agent IO (52%), doublet IO (31%), or IO with non-IO therapy (17%). The median number of IO doses was 8 (range 1-81). At a median follow-up of 12.8 months, 12% of patients (n = 43) had a TE event (venous n = 37 [11%], arterial n = 6 [2%]). The cumulative TE incidence at 6 months was 4.4% (95% confidence interval [CI] 2.6-6.9) and 9.8% (95% CI 6.8-13.4) at 12 months. No factors, including IMDC or Khorana score, were identified to predict TE development. Seventy-two percent of TE resulted in hospitalization (9% TE-related mortality and 21% TE-related dose delay). TE (p < 0.0001), poor IMDC score (p < 0.0001), and Khorana score ≥ 2 (p < 0.0001) were associated with worse OS.Patients with mRCC treated with IO had a high incidence of TE. TE was associated with risk of treatment delay, hospitalization, and mortality, while TE, IMDC poor risk, and Khorana score ≥ 2 were associated with worse survival. Further investigations into IO-associated TE are needed to identify benefit from primary thromboprophylaxis.

  View details for DOI 10.1007/s11523-021-00852-z

  View details for PubMedID 34741719

• Immune Checkpoint Inhibitors Mediated Lymphocytic and Giant Cell Myocarditis: Uncovering Etiological Mechanisms. Frontiers in cardiovascular medicine Rikhi, R., Karnuta, J., Hussain, M., Collier, P., Funchain, P., Tang, W. H., Chan, T. A., Moudgil, R. 2021; 8: 721333

  Abstract

  The advent of immune checkpoint inhibitors (ICIs) has revolutionized the field of oncology, but these are associated with immune related adverse events. One such adverse event, is myocarditis, which has limited the continued immunosuppressive treatment options in patients afflicted by the disease. Pre-clinical and clinical data have found that specific ICI targets and precipitate distinct myocardial infiltrates, consistent with lymphocytic or giant cell myocarditis. Specifically, it has been reported that CTLA-4 inhibition preferentially results in giant cell myocarditis with a predominately CD4+ T cell infiltrate and PD-1 inhibition leads to lymphocytic myocarditis, with a predominately CD8+ T cell infiltrate. Our manuscript discusses the latest literature surrounding ICI pathways and targets, while detailing proposed mechanisms behind ICI mediated myocarditis.

  View details for DOI 10.3389/fcvm.2021.721333

  View details for PubMedID 34434981

  View details for PubMedCentralID PMC8381278

• Incidence of immune checkpoint inhibitor-mediated diarrhea and colitis (imDC) in patients with cancer and preexisting inflammatory bowel disease: a propensity score-matched retrospective study. Journal for immunotherapy of cancer Sleiman, J., Wei, W., Shah, R., Faisal, M. S., Philpott, J., Funchain, P. 2021; 9 (6)

  Abstract

  The risk of use of immune-mediated diarrhea and colitis (imDC) in patients with preexisting inflammatory bowel disease (IBD) is not fully understood. We report the incidence of imDC in these patients, and compare with a matched cohort of patients with cancer and without IBD.Patients with IBD from a tertiary center cancer registry who underwent immune checkpoint inhibitor (ICI) therapy from 2011 to 2019 were identified. A 1:5 matched cohort of patients with and without a history of IBD was created, based on age, ICI therapy, and cancer type. Demographic data, clinical history of IBD, cancer, ICI agent, imDC events after ICI therapy, and overall survival were analyzed. Overall survival and time-to-imDC (TTimDC) were estimated by Kaplan-Meier and multivariate Cox proportional-hazards models.From a retrospective cohort of 3900 patients who received ICI therapy, 30 patients with IBD were matched with 150 patients without a history of IBD. Most patients received PD-1/PD-L1 inhibitor monotherapy (154/180, 85.6%). Individuals with preexisting IBD showed significantly shorter TTimDC than those in the non-IBD group (1-year imDC-free rate 67% vs 93%; HR 7.59, 95% CI 3.00 to 19.15, p<0.0001). Eleven (36%) from the IBD cohort experienced imDC events; none led to life-threatening conditions needing surgical interventions or death. Corticosteroids or biologics were needed in 8/11 (73%) patients, and discontinuation of therapy improved imDC in the remaining three. Half of patients required hospitalization. In contrast, no significant difference in overall survival was observed between IBD and non-IBD cohorts (HR 0.89, 95% CI 0.54 to 1.48). Both groups had overall comparable rates of other non-imDC immune-related adverse events.Patients with preexisting IBD had worse time-to-imDC than non-IBD matched controls, yet did not exhibit worse overall survival. While close monitoring of patients with preexisting IBD is warranted while on immunotherapy, this comorbidity should not preclude ICI therapy if clinically required.

  View details for DOI 10.1136/jitc-2021-002567

  View details for PubMedID 34158318

  View details for PubMedCentralID PMC8220461

• Increased Incidence of Venous Thromboembolism with Cancer Immunotherapy. Med (New York, N.Y.) Roopkumar, J., Swaidani, S., Kim, A. S., Thapa, B., Gervaso, L., Hobbs, B. P., Wei, W., Alban, T. J., Funchain, P., Kundu, S., Sangwan, N., Rayman, P., Pavicic, P. G., Diaz-Montero, C. M., Barnard, J., McCrae, K. R., Khorana, A. A. 2021; 2 (4): 423-434

  Abstract

  Cancer immunotherapy is associated with several immune-related adverse events, but the relationship between immunotherapy and venous thromboembolism has not been thoroughly studied.We conducted a retrospective cohort study of 1,686 patients who received immunotherapy for a variety of malignancies to determine the incidence of venous thromboembolism and the impact of venous thromboembolism on survival. To examine the potential role of inflammation in venous thromboembolism, we also profiled immune cells and plasma cytokines in blood samples obtained prior to initiation of immunotherapy in a sub-cohort of patients treated on clinical trials who subsequently did (N = 15), or did not (N = 10) develop venous thromboembolism.Venous thromboembolism occurred while on immunotherapy in 404/1686 patients (24%) and was associated with decreased overall survival [HR=1.22 (95% CI 1.06-1.41), p<0.008]. Patients that developed venous thromboembolism had significantly higher pretreatment levels of myeloid-derived suppressor cells (5.382 ± 0.873 vs. 3.341 ± 0.3402, mean ± SEM; p=0.0045), interleukin 8 (221.2 ± 37.53 vs. 111.6 ± 25.36, mean ± SEM; p=0.016), and soluble vascular cell adhesion protein 1 (1210 ± 120.6 vs. 895.5 ± 53.34, mean ± SEM; p=0.0385).These findings demonstrate that venous thromboembolism is an underappreciated and important immune-related adverse event associated with cancer immunotherapy, and may implicate an interleukin 8 and myeloid-derived suppressor cell-driven pathway in pathogenesis.

  View details for DOI 10.1016/j.medj.2021.02.002

  View details for PubMedID 34036293

  View details for PubMedCentralID PMC8143033

• Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival. Journal for immunotherapy of cancer Sussman, T. A., Li, H., Hobbs, B., Funchain, P., McCrae, K. R., Khorana, A. A. 2021; 9 (1)

  Abstract

  Thromboembolism (TE) in cancer significantly contributes to morbidity and mortality. Little is known about the incidence of arterial TE (ATE) and venous TE (VTE) in patients with melanoma on immune checkpoint inhibitor (ICI) therapy.We conducted a retrospective cohort study of patients with melanoma receiving ICI from July 2015 through December 2017 at the Cleveland Clinic. TE, including VTE events of deep venous thrombosis, pulmonary embolism, visceral vein thrombosis, and ATE events of myocardial infarction, stroke, peripheral arterial embolism, or transient ischemic attack after ICI initiation were identified. Overall survival (OS) from ICI initiation was estimated by Kaplan-Meier and Cox hazard models; associations between TE, ICI regimen, and clinical risk factors were evaluated using log-rank test.The study population comprised 228 patients with median age of 65 years (23-91 years), 67% male, and median follow-up of 27.3 months. Pembrolizumab was most commonly used (38.7%), followed by combination of ipilimumab plus nivolumab (29.4%), ipilimumab (20%), and nivolumab (12.3%). Most had stage IV disease (81.1%) and 11% had brain metastases (BM) at treatment initiation. Fifty-one TE events occurred in 47 patients (20.6%), including 37 (16.2%) VTE and 14 (6.1%) ATE. Cumulative incidence of TE after ICI initiation was 9.3% (95% CI: 6.0% to 13.6%) at 6 months, and 16.0% (95% CI: 11.6% to 21.2%) at 12 months. The 6-month and 12-month VTE cumulative incidence rates were higher with combination ICI than single agent (16.7% vs 5.0% and 21.3% vs 9.5%, respectively; p=0.02). Risk factors significantly associated with VTE in multivariate analysis included combination ICI (HR 2.70; 95% CI: 1.28 to 5.70; p=0.009), Khorana Score ≥1 (HR 2.24; 95% CI: 1.06 to 4.74; p=0.03), history of coronary artery disease (HR 2.71; 95% CI: 1.16 to 6.29); p=0.02), and anticoagulation at treatment start (HR 4.14; 95% CI: 1.60 to 10.7; p=0.003). Of patients without BM, OS was worse in patients with TE compared with those without (2-year OS 50.8% vs 71.3%; HR 2.27; 95% CI: 1.36 to 3.79; p=0.002), when adjusted for age and stage.ICI is associated with a high incidence of TE in patients with melanoma, with higher rates with combination therapy; TE is associated with substantial worsening of survival. Further studies are needed to identify pathophysiology, biomarkers, and preventive approaches.

  View details for DOI 10.1136/jitc-2020-001719

  View details for PubMedID 33436486

  View details for PubMedCentralID PMC7805375

• Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity. Clinical cancer research : an official journal of the American Association for Cancer Research Gandhi, S., Pandey, M. R., Attwood, K., Ji, W., Witkiewicz, A. K., Knudsen, E. S., Allen, C., Tario, J. D., Wallace, P. K., Cedeno, C. D., Levis, M., Stack, S., Funchain, P., Drabick, J. J., Bucsek, M. J., Puzanov, I., Mohammadpour, H., Repasky, E. A., Ernstoff, M. S. 2021; 27 (1): 87-95

  Abstract

  Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective β-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma.A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months.Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders.Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.

  View details for DOI 10.1158/1078-0432.CCR-20-2381

  View details for PubMedID 33127652

  View details for PubMedCentralID PMC7785669

• Clinical Trials in Metastatic Uveal Melanoma: Current Status. Ocular oncology and pathology Sussman, T. A., Funchain, P., Singh, A. 2020; 6 (6): 381-387

  Abstract

  Uveal melanoma is a rare subtype of melanoma. Prognosis and survival rates for patients with metastatic uveal melanoma remain poor. No current FDA-approved standard of care therapy is available for patients with metastatic uveal melanoma. Thus, clinical trials are essential for the development of new therapies and to provide patients hope for improved survival and outcomes.In this article, we review clinical trials identified on the database https://clinicaltrials.gov that are open and enrolling patients with metastatic uveal melanoma as of November 26, 2019. This search produced 17 active trials involving liver-directed therapy, CNS-directed therapy, and systemic therapy with immunotherapy, targeted therapy, or oncolytic virus therapy. Here, we discuss liver and CNS-directed therapy as well as systemic targeted therapy and oncolytic virus therapy. Immunotherapy clinical trials are discussed in a companion review article by Dr. Marlana Orloff.Various novel therapeutic targets and immunomodulatory approaches are on the horizon for patients with metastatic uveal melanoma and may yield incremental therapeutic benefit. Selecting a clinical trial must be individualized and made jointly with the patient and his/her oncologist.

  View details for DOI 10.1159/000508383

  View details for PubMedID 33447587

  View details for PubMedCentralID PMC7772871

• Systemic Therapy for Melanoma: ASCO Guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Seth, R., Messersmith, H., Kaur, V., Kirkwood, J. M., Kudchadkar, R., McQuade, J. L., Provenzano, A., Swami, U., Weber, J., Alluri, K. C., Agarwala, S., Ascierto, P. A., Atkins, M. B., Davis, N., Ernstoff, M. S., Faries, M. B., Gold, J. S., Guild, S., Gyorki, D. E., Khushalani, N. I., Meyers, M. O., Robert, C., Santinami, M., Sehdev, A., Sondak, V. K., Spurrier, G., Tsai, K. K., van Akkooi, A., Funchain, P. 2020; 38 (33): 3947-3970

  Abstract

  To provide guidance to clinicians regarding the use of systemic therapy for melanoma.ASCO convened an Expert Panel and conducted a systematic review of the literature.A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma.In the adjuvant setting, nivolumab or pembrolizumab should be offered to patients with resected stage IIIA/B/C/D BRAF wild-type cutaneous melanoma, while either of those two agents or the combination of dabrafenib and trametinib should be offered in BRAF-mutant disease. No recommendation could be made for or against the use of neoadjuvant therapy in cutaneous melanoma. In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with BRAF wild-type cutaneous melanoma, while those three regimens or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib should be offered in BRAF-mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. Additional information is available at www.asco.org/melanoma-guidelines.

  View details for DOI 10.1200/JCO.20.00198

  View details for PubMedID 32228358

• Thromboembolism in Patients with Advanced Renal Cell Carcinoma Treated with Immunotherapy Sheng, I., Gupta, S., Reddy, C. A., Angelini, D. E., Funchain, P., Roopkumar, J., Sussman, T. A., Sleiman, J., Gilligan, T. D., Ornstein, M. C., Khorana, A. A. AMER SOC HEMATOLOGY. 2020

  View details for DOI 10.1182/blood-2020-137140

  View details for Web of Science ID 000607205601289

• INCIDENCE OF THROMBOEMBOLISM (TE) IN PATIENTS WITH MELANOMA RECEIVING IMMUNE CHECKPOINT INHIBITOR (ICI) THERAPY AND ITS ADVERSE IMPACT ON SURVIVAL Sussman, T., Roopkumar, J., Li, H., McCrae, K., Funchain, P., Khorana, A. BMJ PUBLISHING GROUP. 2020: A390-A391

  View details for DOI 10.1136/jitc-2020-SITC2020.0649

  View details for Web of Science ID 000616665301169

• SURVIVAL OUTCOMES AND TOXICITY AMONG PATIENTS TREATED WITH CONCOMITANT RADIOTHERAPY AND IMMUNOTHERAPY FOR ADVANCED MELANOMA: TWO FACES OF THE ABSCOPAL EFFECT? Andreatos, N., Roopkumar, J., Khorana, A., Woody, N., Gastman, B., Funchain, P. BMJ PUBLISHING GROUP. 2020: A116

  View details for DOI 10.1136/jitc-2020-SITC2020.0197

  View details for Web of Science ID 000616665300191

• OUTCOMES OF STAGE IV MELANOMA IN THE ERA OF IMMUNOTHERAPY: A NATIONAL CANCER DATABASE (NCDB) ANALYSIS Sussman, T., Wei, W., Funchain, P., Gastman, B. BMJ PUBLISHING GROUP. 2020: A133-A134

  View details for DOI 10.1136/jitc-2020-SITC2020.0224

  View details for Web of Science ID 000616665300218

• Characteristics of Immune Checkpoint Inhibitor-Associated Gastritis: Report From a Major Tertiary Care Center Faisal, M., Sleiman, J., Shah, R. S., Funchain, P., Philpott, J. LIPPINCOTT WILLIAMS & WILKINS. 2020: S679-S680

  View details for Web of Science ID 000607196703262

• Utilization and impact of immunotherapy in stage IV melanoma using the National Cancer Database. Melanoma research Conic, R. R., Knackstedt, R., Sussman, T. A., Rambhia, S., Damiani, G., Funchain, P., Ko, J., Gastman, B. R. 2020; 30 (4): 376-385

  Abstract

  To evaluate factors affecting the utilization of immunotherapy and to stratify results based on the approval of ipilimumab in 2011 and PD-1 inhibitors in 2014, an analysis of available data from the National Cancer Database (NCDB) was performed. Stage IV melanoma patients were identified. Effects of immunotherapy on overall survival (OS) were assessed using Kaplan-Meier curves and Cox proportional hazards model. A total of 19 233 patients were analyzed and 1998 received immunotherapy. Between 2011 and 2013, and in 2014, 18.6 and 28.9% of patients received immunotherapy, respectively. Patients who received immunotherapy from 2011 to 2013 had a 33% (95% CI, 30-35%) 3-year OS compared to 23% (95% CI, 21-24%). In 2014, 3-year OS was 37% (95% CI, 32-43%) for those who received immunotherapy compared to 22% (95% CI, 18-26%) for those who did not (P < 0.0001). This is the first analysis of a large cancer database for melanoma patients with stratification based on utilization and availability of immunotherapy. Immunotherapy increased yearly and improved OS. With combination immunotherapy now more widely employed, it is expected these results will continue to improve. This is the first analysis of a large cancer database for melanoma patients with stratification based on utilization and availability of immunotherapy demonstrating that immunotherapy increased yearly and improved OS.

  View details for DOI 10.1097/CMR.0000000000000672

  View details for PubMedID 32404731

• Targeted next generation sequencing (NGS) to classify melanocytic neoplasms. Journal of cutaneous pathology Zarabi, S. K., Azzato, E. M., Tu, Z. J., Ni, Y., Billings, S. D., Arbesman, J., Funchain, P., Gastman, B., Farkas, D. H., Ko, J. S. 2020; 47 (8): 691-704

  Abstract

  This study piloted a pan-solid-tumor next generation sequence (NGS)-based laboratory developed test as a diagnostic aid in melanocytic tumors. 31 cases (4 "epithelioid" nevi, 5 blue nevi variants, 7 Spitz tumors [3 benign and 4 malignant] and 15 melanomas) were evaluated. All tumors [median diameter 7 mm (range 4-15 mm); median thickness 2.25 mm (range 0.25-12 mm)] yielded satisfactory results. The number of small nucleotide variants/tumor was significantly different between melanoma (median 18/tumor, range 4-71) and all other lesions (median 8/tumor, range 3-17) (P < 0.004) and malignant (median 16/tumor, range 4-71) vs benign lesions (median 7/tumor, range 3-14) (P = 0.01). BRAF, MET, NTRK1, and ROS fusions only occurred in benign Spitz tumors; EML4 fusion, BRAF, MAP2K1 and TERT mutations occurred in malignant Spitz tumors and/or melanoma. Amplifications and NRAS and NF1 mutations only occurred in melanoma. Most melanomas contained >1 pathogenic alteration. Developed NGS-based criteria correctly classified all malignant lesions in this series. 10/12 cases showed concordance with FISH; consensus diagnosis agreed with NGS classification in FISH-non-concordant cases. This pilot study suggests that NGS may be an effective diagnostic adjunct comparable to FISH, but further studies with larger numbers of cases are needed.

  View details for DOI 10.1111/cup.13695

  View details for PubMedID 32291779

• Increased normal tissue telomere length is associated with decreased survival in melanoma patients Ni, Y., Romigh, T., Funchain, P., Arbesman, J. ELSEVIER SCIENCE INC. 2020: S17

  View details for Web of Science ID 000554564400160

• Genetic Counseling and Germline Testing in the Era of Tumor Sequencing: A Cohort Study. JNCI cancer spectrum Klek, S., Heald, B., Milinovich, A., Ni, Y., Abraham, J., Mahdi, H., Estfan, B., Khorana, A. A., Bolwell, B. J., Grivas, P., Sohal, D. P., Funchain, P. 2020; 4 (3): pkaa018

  Abstract

  The clinical impact of addressing potential germline alterations from tumor-only next-generation sequencing (NGS) is not well characterized. Current guidelines for cancer genetic testing may miss clinically actionable germline changes, which may have important implications for cancer screening, treatment, and prevention. We examined whether increasing involvement of the clinical genetics service during somatic tumor-only NGS review at Molecular Tumor Board (MTB) increases the detection of germline findings.In a retrospective evaluation of patients who underwent tumor-only NGS and were reviewed at MTB, we quantified genetic counseling (GC) referrals as well as germline testing uptake and results across three cohorts: before (C1) and after (C2) the addition of tumor-only NGS review and after (C3) instituting a formal process to coordinate NGS-based genetics referrals to preexisting oncology appointments. All statistical tests were two-sided.From 2013 to 2017, 907 tumor-only NGS reports were reviewed at MTB (nC1 = 281, nC2 = 493, nC3 = 133); gastrointestinal (22.5%), lung (19.7%), genitourinary (14.8%), and breast (14.1%) were the most common index cancers. GC visits due to MTB increased with each successive cohort (C1 = 1.1%, C2 = 6.9%, C3 = 13.5%; P for trend [P trend] < .001), as did germline testing (C1 = 0.7%, C2 = 3.2%, C3 = 11.3%; P trend < .001). Diagnosis of germline pathogenic variants increased with each successive cohort (C1 = 1.4%, C2 = 2.0%, C3 = 7.5%; P trend = .003) and with germline pathogenic variants found by MTB review (C1 = 0.4%, C2 = 0.4%, C3 = 2.3%; P trend = .12).Both review of tumor-only NGS by genetics and the institution of a process coordinating GC with oncology appointments increased the discovery of germline pathogenic variants from tumor-only NGS testing. Furthermore, this process identified germline pathogenic variant carriers who would not have otherwise met standard criteria for germline testing.

  View details for DOI 10.1093/jncics/pkaa018

  View details for PubMedID 32596633

  View details for PubMedCentralID PMC7306190

• Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study. Journal for immunotherapy of cancer Najjar, Y. G., Navrazhina, K., Ding, F., Bhatia, R., Tsai, K., Abbate, K., Durden, B., Eroglu, Z., Bhatia, S., Park, S., Chowdhary, A., Chandra, S., Kennedy, J., Puzanov, I., Ernstoff, M., Vachhani, P., Drabick, J., Singh, A., Xu, T., Yang, J., Carvajal, R., Manson, D., Kirkwood, J. M., Cohen, J., Sullivan, R., Johnson, D., Funchain, P., Shoushtari, A. 2020; 8 (1)

  Abstract

  Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined.We conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology.89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%).Dual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate.

  View details for DOI 10.1136/jitc-2019-000331

  View details for PubMedID 32581057

  View details for PubMedCentralID PMC7319717

• Real-world experience of talimogene laherparepvec in patients receiving immunotherapy in metastatic melanoma. Behera, T., Song, J., Ko, J. S., McNamara, M. J., Funchain, P., Gastman, B. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368308253

• Thromboembolism (TE) in patients (pts) with bladder cancer treated with checkpoint inhibitors (CPIs). Sheng, I., Gupta, S., Reddy, C. A., Angelini, D. E., Funchain, P., Sussman, T. A., Sleiman, J., Gilligan, T. D., Ornstein, M., Khorana, A. A. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368302298

• Patterns in progression from early stage melanoma to late stage melanoma: Implications for survivorship follow up. Switzer, B., Savage, D., Song, J., Stanek, C., Funchain, P. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368308476

• A phase II trial of nivolumab in combination with talazoparib in unresectable or metastatic melanoma patients with mutations in BRCA or BRCAness. Sussman, T. A., Wei, W., Hobbs, B., Diaz-Montero, C., Ni, Y., Arbesman, J., Ko, J. S., Gastman, B., Funchain, P. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368309008

• Role of glutamine metabolism in CD8<SUP>+</SUP>PD-1<SUP>+</SUP>TIM-3<SUP>+</SUP> T cells in ICI resistant melanoma. Thapaliya, S., Gastman, B., Phoon, Y., Li, C., Zhou, B., Funchain, P., Richardson, B., Cameron, M., Cameron, C. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368308293

• Immune-mediated adverse events following concomitant radiotherapy and immunotherapy in patients with melanoma and Merkel cell carcinoma: A preliminary report from an evolving retrospective registry. Andreatos, N., Roopkumar, J., Khorana, A. A., Funchain, P. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368301395

• CMV coinfection in treatment refractory immune checkpoint inhibitor colitis. BMJ case reports Harris, K. B., Funchain, P., Baggott, B. B. 2020; 13 (5)

  Abstract

  As immune checkpoint inhibitors (ICIs) are increasingly used, clinicians are more frequently encountering the side effects of these therapies. ICIs have been implicated in numerous adverse effects against healthy tissues. We present a case of a patient who developed treatment refractory checkpoint inhibitor colitis. Following colonoscopy, it was discovered that this patient had cytomegalovirus (CMV) coinfection. This case report highlights the importance of undertaking an appropriate assessment, including endoscopic and histologic investigation, of patients with presumed ICI colitis. Accurately diagnosing a superimposed CMV colitis changes clinical management and can improve patient outcomes.

  View details for DOI 10.1136/bcr-2019-233519

  View details for PubMedID 32434876

  View details for PubMedCentralID PMC7244273

• SINGLE CELL TRANSCRIPTOME ANALYSIS IDENTIFIES UNIQUE FEATURES IN CIRCULATING CD8+T CELLS THAT CAN PREDICT IMMUNOTHERAPY RESPONSE IN MELANOMA PATIENTS Li, C., Phoon, Y., Karlinsey, K., Tian, Y., Thapaliya, S., Qu, L., Cameron, M., Cameron, C., Menoret, A., Funchain, P., Song, J., Diaz-Montero, C., Rodriguez, A., Bonin, C., Vella, A., Zhou, B., Gastman, B. BMJ PUBLISHING GROUP. 2020: A5

  View details for DOI 10.1136/LBA2019.7

  View details for Web of Science ID 000540356400008

• Prognosis of patients developing immune-related adverse events with immune checkpoint inhibitors in melanoma influenced by the ability to resume therapy Song, J., Behera, T., Demski, K., Yurco, A., Patil, P., Funchain, P. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000529994300062

• Venous thromboembolism (VTE) in melanoma patients (pts) on immunotherapy (IO) Sussman, T. A., Roopkumar, J., Li, H., Hobbs, B., Khorana, A. A., Funchain, P. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000529994300090

• Primer on Hereditary Cancer Predisposition Genes Included Within Somatic Next-Generation Sequencing Panels. JCO precision oncology Akras, Z., Bungo, B., Leach, B. H., Marquard, J., Ahluwalia, M., Carraway, H., Grivas, P., Sohal, D. P., Funchain, P. 2019; 3: 1-11

  Abstract

  It has been estimated that 5% to 10% of cancers are due to hereditary causes. Recent data sets indicate that the incidence of hereditary cancer may be as high as 17.5% in patients with cancer, and a notable subset is missed if screening is solely by family history and current syndrome-based testing guidelines. Identification of germline variants has implications for both patients and their families. There is currently no comprehensive overview of cancer susceptibility genes or inclusion of these genes in commercially available somatic testing. We aimed to summarize genes linked to hereditary cancer and the somatic and germline panels that include such genes.Germline predisposition genes were chosen if commercially available for testing. Penetrance was defined as low, moderate, or high according to whether the gene conferred a 0% to 20%, 20% to 50%, or 50% to 100% lifetime risk of developing the cancer or, when percentages were not available, was estimated on the basis of existing literature descriptions.We identified a total of 89 genes linked to hereditary cancer predisposition, and we summarized these genes alphabetically and by organ system. We considered four germline and six somatic commercially available panel tests and quantified the coverage of germline genes across them. Comparison between the number of genes that had germline importance and the number of genes included in somatic testing showed that many but not all germline genes are tested by frequently used somatic panels.The inclusion of cancer-predisposing genes in somatic variant testing panels makes incidental germline findings likely. Although somatic testing can be used to screen for germline variants, this strategy is inadequate for comprehensive screening. Access to genetic counseling is essential for interpretation of germline implications of somatic testing and implementation of appropriate screening and follow-up.

  View details for DOI 10.1200/PO.18.00258

  View details for PubMedID 35100683

• Biomarker Assessment of Venous Thromboembolism in Cancer Patients Receiving Checkpoint Blockade Swaidani, S., Roopkumar, J., Jun-Shim, Y., Charles, C., Paul, S., Kundu, S., Funchain, P., Rayman, P., Pavicic, P. G., Diaz-Montero, C., Khorana, A. A., McCrae, K. R. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-130911

  View details for Web of Science ID 000577164600228

• IMPACT OF KRAS MUTATION STATUS ON THE EFFICACY OF IMMUNOTHERAPY IN LUNG CANCER BRAIN METASTASES Lauko, A., Ali, A., Sagar, S., Barnett, A., Li, H., Chao, S., Stevens, G., Pennell, N., Peereboom, D., Yu, J., Murphy, E., Angelov, L., Funchain, P., Mohammadi, A., Suh, J., Barnett, G., Ahluwalia, M. OXFORD UNIV PRESS INC. 2019: 55

  View details for Web of Science ID 000509478701076

• Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Abu-Sbeih, H., Ali, F. S., Naqash, A. R., Owen, D. H., Patel, S., Otterson, G. A., Kendra, K., Ricciuti, B., Chiari, R., De Giglio, A., Sleiman, J., Funchain, P., Wills, B., Zhang, J., Naidoo, J., Philpott, J., Gao, J., Subudhi, S. K., Wang, Y. 2019; 37 (30): 2738-2745

  Abstract

  Immune checkpoint inhibitor (ICI) therapy often is suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the rate of and risk factors for IMDC recurrence after ICI resumption.This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between January 2010 and November 2018. Univariable and multivariable logistic regression analyses assessed the association of clinical covariates and IMDC recurrence.Of the 167 patients in our analysis, 32 resumed an anti-cytotoxic T-cell lymphocyte-4 (CTLA-4) agent, and 135 an anti-programmed cell death 1 or ligand 1 (PD-1/L1) agent. The median age was 60 years (interquartile range [IQR], 50-69 years). The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136 days). IMDC recurred in 57 patients (34%) overall (44% of those receiving an anti-CTLA-4 and 32% of those receiving an anti-PD-1/L1); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC, and all required permanent discontinuation of ICI therapy. The median duration from ICI resumption to IMDC recurrence was 53 days (IQR, 22-138 days). On multivariable logistic regression, patients who received anti-PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45; 95% CI, 1.59 to 7.69; P = .002). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95% CI, 1.08 to 9.62; P = .019) or had a longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95% CI, 1.00 to 1.03; P = .031). Risk of IMDC recurrence was lower after resumption of anti-PD-1/L1 therapy than after resumption of anti-CTLA-4 therapy (OR, 0.30; 95% CI, 0.11 to 0.81; P = .019).One third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. Recurrence of IMDC was less frequent after resumption of anti-PD-1/L1 than after resumption of anti-CTLA-4.

  View details for DOI 10.1200/JCO.19.00320

  View details for PubMedID 31163011

  View details for PubMedCentralID PMC6800279

• Immune Checkpoint Inhibitor Related Colitis (ICI-Colitis) in Patients With Preexisting Inflammatory Bowel Disease or Microscopic Colitis Sleiman, J., Shah, R., Wei, W., Funchain, P., Philpott, J., Simons-Linares, R. LIPPINCOTT WILLIAMS & WILKINS. 2019: S393

  View details for DOI 10.14309/01.ajg.0000592208.76815.62

  View details for Web of Science ID 000509756001284

• Comparison of head and neck and nonehead and neck Merkel cell carcinoma: Clinicopathologic characteristics, time to treatment initiation, and survival Conic, R., Ko, J., Damiani, G., Funchain, P., Vidimos, A., Gastman, B. MOSBY-ELSEVIER. 2019: AB36

  View details for Web of Science ID 000482195000124

• Sentinel lymph node biopsy in Merkel cell carcinoma: Predictors of sentinel lymph node utilization, positivity and effects on overall survival Conic, R., Ko, J., Damiani, G., Funchain, P., Vidimos, A., Gastman, B. MOSBY-ELSEVIER. 2019: AB122

  View details for Web of Science ID 000482195001090

• Immune Checkpoint Inhibitors-Related Gastrointestinal Toxicity Is Associated With Better Overall Survival and Treatment Response in Cancer Patients Alomari, M., Al Ashi, S., Al Momani, L., Nehme, F., Sarmini, M., Young, M., Funchain, P., Romero-Marrero, C. LIPPINCOTT WILLIAMS & WILKINS. 2019: S552-S553

  View details for Web of Science ID 000509756002171

• Variations of Diagnosis and Management of Immune Checkpoint Inhibitor Pancreatic Injury (ICIPI) and Immune Checkpoint Inhibitor Pancreatitis: A Single Institution Experience Shah, R., Sleiman, J., Simons-Linares, R., Faisal, M., Song, J., Philpott, J., Funchain, P. LIPPINCOTT WILLIAMS & WILKINS. 2019: S58

  View details for DOI 10.14309/01.ajg.0000589904.13719.5f

  View details for Web of Science ID 000509756000094

• The paradox of melanoma in oculocutaneous albinism: A case report and literature review Ravichandran, S., Funchain, P., Arbesman, J. ELSEVIER SCIENCE INC. 2019: B21

  View details for DOI 10.1016/j.jid.2019.06.093

  View details for Web of Science ID 000482187300113

• Pre-treated anti-PD-1 refractory Merkel cell carcinoma successfully treated with the combination of PD-1/PD-L1 axis inhibitors and TVEC: a report of two cases ANNALS OF ONCOLOGY Knackstedt, R., Sussman, T. A., McCahon, L., Song, J., Funchain, P., Gastman, B. 2019; 30 (8): 1399-1400

  View details for DOI 10.1093/annonc/mdz187

  View details for Web of Science ID 000493072600030

  View details for PubMedID 31250007

• Sentinel lymph node biopsy in Merkel cell carcinoma: Predictors of sentinel lymph node positivity and association with overall survival. Journal of the American Academy of Dermatology Conic, R. R., Ko, J., Saridakis, S., Damiani, G., Funchain, P., Vidimos, A., Gastman, B. R. 2019; 81 (2): 364-372

  Abstract

  Merkel cell carcinoma (MCC) is a rare, aggressive malignancy with high rates of recurrence and metastasis.To evaluate predictors of sentinel lymph node (SLN) positivity in MCC using the National Cancer Database.The National Cancer Database, from 2012 to 2014, was used to identify 3048 patients with MCC, of whom 1174 received an SLN biopsy. Predictors of SLN positivity were evaluated using logistic regression. Overall survival was evaluated using a Cox proportional hazards model.Of patients who underwent SLN biopsy, those with primary lesions on the trunk (odds ratio, 1.98; 95% confidence interval [CI], 1.23-3.17; P = .004), tumor-infiltrating lymphocytes (odds ratio, 1.58; 95% CI, 1.01-2.46; P = .04), or lymphovascular invasion (odds ratio, 3.45; 95% CI, 2.51-4.76; P < .001) were more likely to have positive SLNs on multivariate analysis. Overall survival was negatively affected by age ≥75 years (hazard ratio [HR], 2.55; 95% CI, 1.36-4.77; P = .003), male sex (HR, 1.78; 95% CI, 1.09-2.91, P = .022), immunosuppression (HR, 3.51; 95% CI, 1.72-7.13; P = .001), and SLN positivity (HR, 3.15; 95% CI, 1.98-5.04; P < .001).Lack of disease-specific survival and potential selection bias from a retrospective data set.Truncal MCC, tumor-infiltrating lymphocytes, and presence of lymphovascular invasion were independent predictors of positive SLNs. Overall survival was negatively affected by advancing age, male sex, immunosuppression, and SLN positivity.

  View details for DOI 10.1016/j.jaad.2019.03.027

  View details for PubMedID 30902726

• Uveal Melanoma Metastatic to the Liver: Treatment Trends and Outcomes. Ocular oncology and pathology Xu, L. T., Funchain, P. F., Bena, J. F., Li, M., Tarhini, A., Berber, E., Singh, A. D. 2019; 5 (5): 323-332

  Abstract

  To describe treatment trends and outcomes of liver metastasis from uveal melanoma.Retrospective case series of 73 patients with uveal melanoma liver metastasis. Patients were treated first-line with systemic therapy (not including checkpoint inhibitors), checkpoint inhibitors, local therapy or no treatment. Time to metastasis, detection method, and survival data were collected. Time periods were divided between 2004-2011 and 2012-2016. Cox proportional hazards models were used to compare progression-free survival (PFS) and overall survival (OS).Median PFS and OS for the entire cohort was 4 months (95% CI 3-5) and 15 months (95% CI 11-18), respectively. There was no statistically significant difference in PFS and OS across the two time periods. Patients who received no treatment had the shortest OS (median 4.9 months), whereas those treated with local therapy had the longest PFS (median 4.6 months) and OS (median 18.7 months). Having liver metastasis diagnosed by symptoms was associated with a greater risk of mortality (p < 0.001).Patients who received first-line local treatment had the longest PFS and OS, while patients who received no treatment had the shortest OS. Survival outcomes did not improve for patients including those receiving check point inhibitors.

  View details for DOI 10.1159/000495113

  View details for PubMedID 31559243

  View details for PubMedCentralID PMC6751472

• Immune Checkpoint Inhibitors Associated with Cardiotoxicity in Cancer Patients: A Large Single-Center Experience Chahine, J., Thapa, B., Ala, C. K., Patil, P., Funchain, P., Maroo, A., Klein, A. L., Tang, W. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2019: S63

  View details for DOI 10.1016/j.cardfail.2019.07.179

  View details for Web of Science ID 000482698000166

• Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials (vol 125, pg 18, 2019) CANCER Jeter, J. M., Bowles, T. L., Curiel-Lewandrowski, C., Swetter, S. M., Filipp, F. V., Abdel-Malek, Z. A., Geskin, L. J., Brewer, J. D., Arbiser, J. L., Gershenwald, J. E., Chu, E. Y., Kirkwood, J. M., Box, N. F., Funchain, P., Fisher, D. E., Kendra, K. L., Marghoob, A. A., Chen, S. C., Ming, M. E., Albertini, M. R., Vetto, J. T., Margolin, K. A., Pagoto, S. L., Hay, J. L., Grossman, D., Ellis, D. L., Kashani-Sabet, M., Mangold, A. R., Markovic, S. N., Meyskens, F. L., Nelson, K. C., Powers, J. G., Robinson, J. K., Sahni, D., Sekulic, A., Sondak, V. K., Wei, M. L., Zager, J. S., Dellavalle, R. P., Thompson, J. A., Weinstock, M. A., Leachman, S. A., Cassidy, P. B. 2019; 125 (15): 2706

  View details for DOI 10.1002/cncr.32075

  View details for Web of Science ID 000475478300024

• Clonal hematopoiesis of indeterminate potential (CHIP) mutations in solid tumor malignancies. Conces, M., Ni, Y., Bazeley, P., Patel, B., Funchain, P., Carraway, H. E. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.1507

  View details for Web of Science ID 000487345804303

• Incidence and clinical pattern of immune related adverse effects (irAE) due to immune checkpoint inhibitors (ICI). Thapa, B., Roopkumar, J., Kim, A. S., Gervaso, L., Patil, P., Calabrese, C., Khorana, A. A., Funchain, P. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.e14151

  View details for Web of Science ID 000487345800524

• Immune-mediated colitis after resumption of immune checkpoint inhibitor therapy. Abu-Sbeih, H., Ali, F., Naqash, A., Owen, D., Patel, S. H., Otterson, G., Kendra, K., Ricciuti, B., Chiari, R., De Giglio, A., Sleiman, J., Funchain, P., Beatriz, W., Zhang, J., Naidoo, J., Philpott, J., Gao, J., Subudhi, S., Wang, Y. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.2577

  View details for Web of Science ID 000487345804527

• Prognostic Significance of "Nonsolid" Microscopic Metastasis in Merkel Cell Carcinoma Sentinel Lymph Nodes. The American journal of surgical pathology Erstine, E. M., Tetzlaff, M. T., Jia, X., Aung, P. P., Prieto, V. G., Funchain, P., Gastman, B. R., Billings, S. D., Ko, J. S. 2019

  Abstract

  Our recent work regarding Merkel cell carcinoma sentinel lymph node (SLN) metastasis found that "solid" pattern microscopic metastasis conferred worse prognosis than the "nonsolid" ones. The goals of the present study were to (1) compare the prognostic significance/outcomes of 2 diagnostic groups-patients with a nonsolid pattern of SLN metastasis and those with diagnostically negative SLN biopsies (SLNB), and (2) evaluate the durability of SLN metastasis after extensive sectioning. Five-level, step-wise sectioning at 250-μm intervals was performed in all SLN blocks with an immunohistochemical stain for CK20 on all levels. The presence and pattern of metastases were recorded and analyzed as were corresponding patient and tumor parameters. Median follow-up durations for all patients (n=38), positive SLNB (n=16) and negative SLNB (n=22) groups were 56.3, 50.4, and 66.8 months, respectively. Overall survival (OS) and disease-specific survival (DSS) did not differ between the 2 diagnostic groups (OS P=0.65, DSS P=0.37) but did differ by immune status (immunocompetent vs. immunosuppressed, OS P=0.03, DSS P=0.005) and primary tumor category (OS P<0.0001, DSS P=0.001). On deeper sectioning, all 16 diagnostically positive SLNB continued to show nonsolid microscopic metastasis, and 32% (7/22) diagnostically negative SLNB revealed nonsolid metastasis. DSS was worse for sinusoidal-pattern metastasis versus all others (P=0.02). Five of 38 patients (13%) died of disease; the only immunocompetent patient had sinusoidal-pattern metastasis discovered in a diagnostically negative SLNB. Our data suggest that outcome for nonsolid metastasis is similar to that of negative SLNB with the exception of the sinusoidal pattern, which was associated with worse outcome. Larger studies are warranted to quantify and compare microscopic metastatic tumor burden by pattern and confirm whether the sinusoidal pattern confers an intermediate prognostic risk between solid and other nonsolid microscopic metastases.

  View details for DOI 10.1097/PAS.0000000000001277

  View details for PubMedID 31094923

• Low-dose IL-12 preconditions the tumor microenvironment to enhance the efficacy of PD-1 blockade. Diaz-Montero, C., Ravichandran, S., Pavicic, P. G., Rayman, P. A., Tannenbaum, C., Finke, J., Ko, J. S., Funchain, P., Tarhini, A. A. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.8_suppl.20

  View details for Web of Science ID 000489109600036

• THE MICROBIOME OF TEMPORAL ARTERIES Hoffman, G. S., Getz, T. M., Padmanabhan, R., Villa-Forte, A., Calabrese, L. H., Clifford, A. H., Funchain, P., Sankhunny, M., Perry, J. D., Blandford, A., Kosmorsky, G., Lystad, L., Eng, C. OXFORD UNIV PRESS. 2019

  View details for Web of Science ID 000478085100184

• Decreased T-Cell Programmed Death Receptor-1 Expression in Pregnancy-Associated Melanoma. The American Journal of dermatopathology Ko, J. S., Gastman, B. R., Conic, R., Tellez Diaz Trujillo, A., Diaz-Montero, C. M., Billings, S. D., Tarhini, A., Funchain, P., Atanaskova Mesinkovska, N. 2019; 41 (3): 180-187

  Abstract

  Pregnancy depends on tolerance of an immunologically foreign fetus through type 1 T-cell suppression. Worse melanoma outcomes have been described within 1 year of childbirth. We assessed immunopathologic factors that may account for the observed negative impact of pregnancy on outcome.Women of child-bearing age with ≥24 months follow-up were identified from our Institutional Melanoma Registry. Women with available primary tumor blocks were compared [history of childbirth within 1 year of diagnosis (CB1Y) (n = 18) vs. nonpregnant age-matched controls (n = 13)]. Immunohistochemical staining with quantification of immune infiltrates: CD68 tumor-associated macrophages, CD3 tumor-infiltrating T cells, and PD-1 activated/exhausted T cells; and hematolymphangiogenesis: CD31/D2-40 blood vessels and D2-40 lymphatics was performed by 2 blinded dermatopathologists.CB1Y tumors showed decreased CD3 tumor-infiltrating T cells (P < 0.05) with significantly reduced PD1 expression (P ≤ 0.05). The CD3:PD1 ratio was higher in CB1Y (P < 0.05). Other tested parameters did not significantly differ between the 2 groups.As PD1 expression is induced during type 1 T-cell activation, these data suggest that immune ignorance or suppression may predominate in CB1Y. Further studies are required to identify interventions that may promote tumor-associated T-cell inflammation in such patients.

  View details for DOI 10.1097/DAD.0000000000001286

  View details for PubMedID 30308543

• The Microbiome of Temporal Arteries. Pathogens & immunity Hoffman, G. S., Getz, T. M., Padmanabhan, R., Villa-Forte, A., Clifford, A. H., Funchain, P., Sankunny, M., Perry, J. D., Blandford, A., Kosmorsky, G., Lystad, L., Calabrese, L. H., Eng, C. 2019; 4 (1): 21-38

  Abstract

  A role for microorganisms in giant cell arteritis (GCA) has long been suspected. We describe the microbiomes of temporal arteries from patients with GCA and controls.Temporal artery biopsies from patients suspected to have GCA were collected under aseptic conditions and snap-frozen. Fluorescence in situ hybridization (FISH) and long-read 16S rRNA-gene sequencing was used to examine microbiomes of temporal arteries. Taxonomic classification of bacterial sequences was performed to the genus level and relative abundances were calculated. Microbiome differential abundances were analyzed by principal coordinate analysis (PCoA) with comparative Unifrac distances and predicted functional profiling using PICRUSt.Forty-seven patients, including 9 with biopsy-positive GCA, 15 with biopsy-negative GCA and 23 controls without GCA, were enrolled. FISH for bacterial DNA revealed signal in the arterial media. Beta, but not alpha, diversity differed between GCA and control temporal arteries (P = 0.042). Importantly, there were no significant differences between biopsy-positive and biopsy-negative GCA (P > 0.99). The largest differential abundances seen between GCA and non-GCA temporal arteries included Proteobacteria (P), Bifidobacterium (g), Parasutterella (g), and Granulicatella (g) [Log 2-fold change ≥ 4].Temporal arteries are not sterile, but rather are inhabited by a community of bacteria. We have demonstrated that there are microbiomic differences between GCA and non-GCA temporal arteries, but not between biopsy-positive and biopsy-negative GCA.

  View details for DOI 10.20411/pai.v4i1.270

  View details for PubMedID 30993251

  View details for PubMedCentralID PMC6423729

• A multi-institutional study assessing prevalence of deleterious germline mutations in pancreatic cancer Sadaps, M., Funchain, P., Heald, B., Huether, R., Pitt, J., White, K., Khorana, A. A., Sohal, D. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.4_suppl.280

  View details for Web of Science ID 000489107600311

• Predictors of sentinel lymph node positivity in thin melanoma using the National Cancer Database. Journal of the American Academy of Dermatology Conic, R. R., Ko, J., Damiani, G., Funchain, P., Knackstedt, T., Vij, A., Vidimos, A., Gastman, B. R. 2019; 80 (2): 441-447

  Abstract

  Sentinel lymph node biopsy (SLNB) specimens are often obtained from patients for further staging after these patients have undergone melanoma excision. Limited data regarding predictors of SLNB positivity in thin melanoma are available.We sought to evaluate predictors of SLNB positivity in thin melanoma.Patients with cutaneous melanoma with a Breslow thickness ≤1.00 mm who received a SLNB were identified from the National Cancer Database between 2004 and 2014 (n = 9186). Predictors of SLNB positivity were analyzed using logistic regression.In a multivariate analysis, patients <60 years of age (P < .001) and Breslow thickness >0.8 mm (P = .03) were at increased risk for positive sentinel lymph node (SLN). Moreover, on multivariate analysis, the presence of dermal mitoses increased the odds of SLN positivity by 95% (odds ratio [OR] 1.95 [95% confidence interval {CI} 1.53-2.5], P < .001), ulceration by 63% (OR 1.63 [95% CI 1.21-2.18], P < .001), and Clark level IV to V by 48% (OR 1.48 [95% CI 1.19-1.85]). Patients without ulceration but with dermal mitoses had 92% (OR 1.92 [95% CI 1.5-2.48], P < .001) increased SLN positivity.Limited survival data are available.Younger age, a Breslow thickness >0.8 mm, the presence of dermal mitoses, ulceration, and Clark level IV to V are positive predictors of positive SLN. While the new American Joint Committee on Cancer system has removed dermal mitotic rate from staging, continued evaluation of dermal mitotic rate could be valuable for guiding surgical decision making about SLNB.

  View details for DOI 10.1016/j.jaad.2018.08.051

  View details for PubMedID 30240775

• Immune Check Point Inhibitor-Associated Glomerulonephritis. Kidney international reports Ashour, T., Nakhoul, G., Patil, P., Funchain, P., Herlitz, L. 2019; 4 (2): 355-359

  View details for DOI 10.1016/j.ekir.2018.10.017

  View details for PubMedID 30775635

  View details for PubMedCentralID PMC6365371

• Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials CANCER Jeter, J. M., Bowles, T. L., Curiel-Lewandrowski, C., Swetter, S. M., Filipp, F. V., Abdel-Malek, Z. A., Geskin, L. J., Brewer, J. D., Arbiser, J. L., Gershenwald, J. E., Chu, E. Y., Kirkwood, J. M., Box, N. F., Funchain, P., Fisher, D. E., Kendra, K. L., Marghoob, A. A., Chen, S. C., Ming, M. E., Albertini, M. R., Vetto, J. T., Margolin, K. A., Pagoto, S. L., Hay, J. L., Grossman, D., Ellis, D. L., Kashani-Sabet, M., Mangold, A. R., Markovic, S. N., Nelson, K. C., Powers, J. G., Robinson, J. K., Sahni, D., Sekulic, A., Sondak, V. K., Wei, M. L., Zager, J. S., Dellavalle, R. P., Thompson, J. A., Weinstock, M. A., Leachman, S. A., Cassidy, P. B. 2019; 125 (1): 18–44

  View details for DOI 10.1002/cncr.31719

  View details for Web of Science ID 000454094000006

• Cases from the irAE Tumor Board: A Multidisciplinary Approach to a Patient Treated with Immune Checkpoint Blockade Who Presented with a New Rash. The oncologist Patil, P. D., Fernandez, A. P., Velcheti, V., Tarhini, A., Funchain, P., Rini, B., Khasawneh, M., Pennell, N. A. 2019; 24 (1): 4-8

  Abstract

  Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigms for a broad spectrum of malignancies. Because immune checkpoint inhibitors rely on immune reactivation to eliminate cancer cells, they can also lead to the loss of immune tolerance and result in a wide range of phenomena called immune-related adverse events (irAEs). At our institution, the management of irAEs is based on multidisciplinary input obtained at an irAE tumor board that facilitates expedited opinions from various specialties and allows for a more uniform approach to these patients. In this article, we describe a case of a patient with metastatic urothelial carcinoma who developed a maculopapular rash while being treated with a programmed death-ligand 1 inhibitor. We then describe the approach to management of dermatologic toxicities with ICIs based on the discussion at our irAE Tumor Board. KEY POINTS: Innocuous symptoms such as pruritis or a maculopapular rash may herald potentially fatal severe cutaneous adverse reactions (SCARs); therefore, close attention must be paid to the symptoms, history, and physical examination of all patients.Consultation with dermatology should be sought for patients with grade 3 or 4 toxicity or SCARs and prior to resumption of immune checkpoint inhibitors for patients with grade 3 or higher toxicity.A multidisciplinary immune-related adverse events (irAE) tumor board can facilitate timely input and expertise from various specialties, thereby ensuring a streamlined approach to management of irAEs.

  View details for DOI 10.1634/theoncologist.2018-0434

  View details for PubMedID 30355774

  View details for PubMedCentralID PMC6324641

• Precision Oncology in Solid Tumors: A Longitudinal Tertiary Care Center Experience. JCO precision oncology Sadaps, M., Funchain, P., Mahdi, H., Grivas, P., Pritchard, A., Klek, S., Estfan, B., Abraham, J., Budd, G. T., Stevenson, J. P., Pennell, N. A., Khorana, A. A., Bolwell, B. J., Sohal, D. P. 2018; 2: 1-11

  Abstract

  Precision oncology is widely discussed, but cohort studies are limited. We previously reported our prospective experience of precision oncology in solid tumors, and here we report our longitudinal experience, focusing on therapeutic impact.We conducted a retrospective review of 600 consecutive patients seen at Cleveland Clinic from 2013 to 2016 for treatment of incurable solid tumor malignancies for whom tumor genomic profiling was ordered using FoundationOne (Cambridge, MA). Results were discussed at our multidisciplinary genomics tumor board. Data analyzed included subsequent therapy and overall survival (OS).Median age was 59 years (range, 18 to 94 years), 308 (51.3%) were female, and 533 (88.8%) were white. Targeted therapy was recommended in 310 patients (51.7%). After results, 313 patients (52.2%) started any subsequent therapy; of these, 95 (30%; 15.8% overall) received genomics-driven therapy (G), and 218 (70%) received non-genomics-driven treatment (NG). For the G versus NG group, the on-label, off-label, and clinical trial therapy breakdowns were 23% versus 88%, 47% versus 3%, and 30% versus 9%, respectively. Median OS for patients receiving no therapy after tumor genomic profiling was 5.5 months; for the G and NG groups, it was 18 (P < .001) and 14.4 (P < .001) months, respectively (P = NS for G v NG). The use of G increased from 10% in the first 250-patient cohort (reported earlier) to 20% in the subsequent 350-patient cohort.Tumor genomic profiling influenced treatment in 15.8% of patients. More patients received treatment via clinical trials in the G cohort, and although not statistically significant, there was a trend toward increased OS in the G (v NG) group. These data can further guide real-world applications of precision oncology.

  View details for DOI 10.1200/PO.18.00186

  View details for PubMedID 35135160

• Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research Johnson, D. B., Bordeaux, J., Kim, J. Y., Vaupel, C., Rimm, D. L., Ho, T. H., Joseph, R. W., Daud, A. I., Conry, R. M., Gaughan, E. M., Hernandez-Aya, L. F., Dimou, A., Funchain, P., Smithy, J., Witte, J. S., McKee, S. B., Ko, J., Wrangle, J. M., Dabbas, B., Tangri, S., Lameh, J., Hall, J., Markowitz, J., Balko, J. M., Dakappagari, N. 2018; 24 (21): 5250-5260

  Abstract

  Purpose: PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response.Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti-PD-1 treatment outcomes.Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti-PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival.Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250-60. ©2018 AACR.

  View details for DOI 10.1158/1078-0432.CCR-18-0309

  View details for PubMedID 30021908

  View details for PubMedCentralID PMC6214750

• The Impact of a Novel Immune Related Adverse Event Tumor Board on Interprofessional Clinical Confidence and Collaboration Calabrese, C., Funchain, P., Patil, P. D., Calabrese, L. H. WILEY. 2018

  View details for Web of Science ID 000447268900179

• How should we diagnose and manage checkpoint inhibitor-associated colitis? Cleveland Clinic journal of medicine Khan, F., Funchain, P., Bennett, A., Hull, T. L., Shen, B. 2018; 85 (9): 679-683

  View details for DOI 10.3949/ccjm.85a.18020

  View details for PubMedID 30192732

• Melanoma cases demonstrate increased carrier frequency of phenylketonuria/hyperphenylalanemia mutations. Pigment cell & melanoma research Arbesman, J., Ravichandran, S., Funchain, P., Thompson, C. L. 2018; 31 (4): 529-533

  Abstract

  Identifying novel melanoma genetic risk factors informs screening and prevention efforts. Mutations in the phenylalanine hydroxylase gene (the causative gene in phenylketonuria) lead to reduced pigmentation in untreated phenylketonuria patients, and reduced pigmentation is associated with greater melanoma risk. Therefore, we sought to characterize the relationship between phenylketonuria carrier status and melanoma risk. Using National Newborn Screening Reports, we determined the United States phenylketonuria/hyperphenylalanemia carrier frequency in Caucasians to be 1.76%. We examined three publically available melanoma datasets for germline mutations in the phenylalanine hydroxylase gene associated with classic phenylketonuria and/or hyperphenylalanemia. Mutations were identified in 29/814 melanoma patients, with a carrier frequency of 3.56%. There was a twofold enrichment (p-value = 3.4 × 10-5 ) compared to the Caucasian frequency of hyperphenylalanemia/phenylketonuria carriers. These data demonstrate a novel association between phenylalanine hydroxylase carrier status and melanoma risk. Further, functional investigation is warranted to determine the link between phenylalanine hydroxylase mutations and melanomagenesis.

  View details for DOI 10.1111/pcmr.12695

  View details for PubMedID 29473999

  View details for PubMedCentralID PMC6013363

• Melanoma brain metastasis: the impact of stereotactic radiosurgery, BRAF mutational status, and targeted and/or immune-based therapies on treatment outcome. Journal of neurosurgery Kotecha, R., Miller, J. A., Venur, V. A., Mohammadi, A. M., Chao, S. T., Suh, J. H., Barnett, G. H., Murphy, E. S., Funchain, P., Yu, J. S., Vogelbaum, M. A., Angelov, L., Ahluwalia, M. S. 2018; 129 (1): 50-59

  Abstract

  OBJECTIVE The goal of this study was to investigate the impact of stereotactic radiosurgery (SRS), BRAF status, and targeted and immune-based therapies on the recurrence patterns and factors associated with overall survival (OS) among patients with melanoma brain metastasis (MBM). METHODS A total of 366 patients were treated for 1336 MBMs; a lesion-based analysis was performed on 793 SRS lesions. The BRAF status was available for 78 patients: 35 had BRAF mut and 43 had BRAF wild-type ( BRAF-WT) lesions. The Kaplan-Meier method evaluated unadjusted OS; cumulative incidence analysis determined the incidences of local failure (LF), distant failure, and radiation necrosis (RN), with death as a competing risk. RESULTS The 12-month OS was 24% (95% CI 20%-29%). On multivariate analysis, younger age, lack of extracranial metastases, better Karnofsky Performance Status score, and fewer MBMs, as well as treatment with BRAF inhibitors (BRAFi), anti-PD-1/CTLA-4 therapy, or cytokine therapy were significantly associated with OS. For patients who underwent SRS, the 12-month LF rate was lower among those with BRAF mut lesions (6%, 95% CI 2%-11%) compared with those with BRAF-WT lesions (22%, 95% CI 13%-32%; p < 0.01). The 12-month LF rates among lesions treated with BRAFi and PD-1/CTLA-4 agents were 1% (95% CI 1%-4%) and 7% (95% CI 1%-13%), respectively. On multivariate analysis, BRAF inhibition within 30 days of SRS was protective against LF (HR 0.08, 95% CI 0.01-0.55; p = 0.01). The 12-month rates of RN were low among lesions treated with BRAFi (0%, 95% CI 0%-0%), PD-1/CTLA-4 inhibitors (2%, 95% CI 1%-5%), and cytokine therapies (6%, 95% CI 1%-13%). CONCLUSIONS Prognostic schema should incorporate BRAFi or immunotherapy status and use of targeted therapies. Treatment with a BRAF inhibitor within 4 weeks of SRS improves local control without an increased risk of RN.

  View details for DOI 10.3171/2017.1.JNS162797

  View details for PubMedID 28799876

• Multiplex germline testing in selected melanomas presenting to oncology clinic Funchain, P., Heald, B., Song, J., Nizialek, E., Marquard, J., McNamara, M. J., Tarhini, A. A., Gastman, B., Arbesman, J. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.1588

  View details for Web of Science ID 000442916001205

• Germline variants from paired somatic-germline testing in pancreatic cancer. Funchain, P., Heald, B., White, K., Buschmann, M., Roggin, K. K., Khorana, A. A., Sohal, D. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.e16259

  View details for Web of Science ID 000442916005362

• Genetic counseling (GC) and germline (GL) testing rates after adoption of an integrated clinical cancer genetics (CCG) approach to genomics tumor board (GTB). Klek, S., Heald, B., Milinovich, A., Ni, Y., Abraham, J., Grivas, P., Mahdi, H., Khorana, A. A., Bolwell, B., Sohal, D., Funchain, P. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.1511

  View details for Web of Science ID 000442916001133

• Longitudinal precision oncology experience in solid tumors at the Cleveland Clinic. Sadaps, M., Funchain, P., Mahdi, H., Grivas, P., Pritchard, A., Klek, S., Estfan, B. N., Abraham, J., Budd, G., Stevenson, J., Pennell, N. A., Khorana, A. A., Bolwell, B., Sohal, D. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.e18710

  View details for Web of Science ID 000442916006095

• Talimogene Laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III-IV melanoma: a case series. Journal for immunotherapy of cancer Sun, L., Funchain, P., Song, J. M., Rayman, P., Tannenbaum, C., Ko, J., Mcnamara, M., Marcela Diaz-Montero, C., Gastman, B. 2018; 6 (1): 36

  Abstract

  Talimogene Laherparepvec (T-VEC) is an oncolytic virus approved as an intratumoral therapy for treating unresectable stage IIIB-IV metastatic melanoma. The mechanisms of action for T-VEC and checkpoint inhibitor are highly complementary. Recent studies have shown that combining checkpoint inhibitor therapy with T-VEC injection can lead to improved response rates for stage IIIB-IV melanoma patients.We reviewed 10 consecutive cases of stage IIIC to stage IVM1b melanoma patients that received T-VEC plus checkpoint inhibitor(s) therapy (pembrolizumab, ipilimumab/nivolumab, or nivolumab) treated between June 2016 and August 2017 at the Cleveland Clinic with a median follow-up of 7 months (range: 4 to 13 months). Responses of injected (on-target) and uninjected (off-target) lesions were evaluated according to RECIST 2.0.The overall response rate for on-target lesions was 90%, with 6 patients experiencing a complete response in injected lesions. Two patients had off-target lesions, which were completely resolved after treatment. Blood samples were tested for 3 complete responders and 2 partial responders. CD4:CD8 ratio and frequencies of circulating PD1+ CD4 and CD8 T cells were elevated in complete responders but not partial responders. One patient died due to causes unrelated to melanoma and one patient died of progression of the disease.Our data suggest that combining checkpoint inhibitor(s) with T-VEC injection may provide a synergistic efficacy for patients with unresectable melanoma. We observed a better overall response rate and complete response rate compared to published studies on similar therapeutic regimens.

  View details for DOI 10.1186/s40425-018-0337-7

  View details for PubMedID 29764498

  View details for PubMedCentralID PMC5954455

• Prognostic value of sentinel lymph node biopsy according to Breslow thickness for cutaneous melanoma. Journal of the American Academy of Dermatology Stiegel, E., Xiong, D., Ya, J., Funchain, P., Isakov, R., Gastman, B., Vij, A. 2018; 78 (5): 942-948

  Abstract

  Sentinel lymph node (SLN) biopsy is widely performed for melanoma with certain histologic parameters and offers important prognostic and staging information. Breslow thickness (BT) by itself also provides meaningful prognostic information.To evaluate whether SLN status provides prognostic information independent from that which is already provided by BT.We conducted a retrospective cohort study of 896 patients who underwent SLN biopsy for primary cutaneous melanoma. Stratified analysis of the impact of SLN status within BT groups (0.01-1 mm, 1.01-2.00 mm, 2.01-4.00 mm, and >4.00 mm) was performed. In addition, a Cox proportional hazard model was fit to evaluate the interaction between BT unadjusted and then adjusted for SLN status to determine whether predictive ability is improved.Having a negative SLN did not confer a statistically significant survival advantage for any BT subgroup (P = .54, .075, .17, and .95 for subgroups 0.01-1 mm, 1.01-2.00 mm, 2.01-4.00 mm, and >4.00 mm, respectively). In multivariate analysis, SLN status did not demonstrate independent prognostic ability over that of BT alone (P = .067).Retrospective study, single institution.Our data suggest that SLN status does not offer better prognostic information for patients than BT alone.

  View details for DOI 10.1016/j.jaad.2018.01.030

  View details for PubMedID 29408526

• Posterior Reversible Encephalopathy Syndrome during Treatment with Lenvatinib Khoury, J., Funchain, P. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090802406

• Shared medical appointment for early stage melanoma survivorship Funchain, P., Song, J., Stanek, C., McNamara, M. J., Tarhini, A. A., Gastman, B., Marcus, J. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.7_suppl.69

  View details for Web of Science ID 000443285600068

• Using Genomic Sequencing to Improve Management in Melanoma ONCOLOGY-NEW YORK Funchain, P., Tarhini, A. A. 2018; 32 (3): 98-+

  Abstract

  Rapidly advancing genomic sequencing technologies are changing all areas of cancer, from diagnosis to surveillance, and prognostication to treatment. The role of genomic testing in melanoma is expanding, and multiple genomically based tests are available, including somatic tumor sequencing for actionable genetic alterations and tumor mutational burden, prognostic gene expression profiling from tumor tissue, and germline genetic testing from blood. The available testing options have varying levels of supporting data, from robust to preliminary. Here we summarize the available genomic and genetic tests for melanoma, and the level of evidence supporting each of these. We also discuss the current impact of genomic sequencing on the management of melanoma, as well as roles it may play in the near future.

  View details for Web of Science ID 000427603900003

  View details for PubMedID 29548064

• Single center experience of dermatologic and oncologic surveillance patterns for late stage melanomas that progressed from early stage melanoma. Song, J., Marcus, J., Stanek, C., McNamara, M. J., Gastman, B., Tarhini, A. A., Funchain, P. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.7_suppl.182

  View details for Web of Science ID 000443285600174

• Response to platinum-based therapy (PBT) and immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC) patients (pts) with genomic alterations (GA) in homologous recombination repair (HRR) genes Mendiratta, P., Loehr, A., Simmons, A., Barata, P. C., Klek, S., Pritchard, A., Emamekhoo, H., Funchain, P., Sohal, D., Ali, S., Gilligan, T. D., Ornstein, M., Garcia, J. A., Rini, B. I., Grivas, P. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for DOI 10.1200/JCO.2018.36.6_suppl.447

  View details for Web of Science ID 000436179500441

• Talimogene Laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III-IV melanoma: a case series Sun, L., Funchain, P., Song, J., McNamara, M., Gastman, B. BMC. 2017

  View details for Web of Science ID 000460207200073

• Outcomes Following Spine Stereotactic Radiosurgery for the Treatment of Melanoma Spine Metastases Tom, M. C., Yang, K., Balagamwala, E. H., Angelov, L., Mohammadi, A. M., McNamara, M., Funchain, P., Suh, J. H., Chao, S. T. ELSEVIER SCIENCE INC. 2017: E528

  View details for DOI 10.1016/j.ijrobp.2017.06.1868

  View details for Web of Science ID 000411559104133

• Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance ANNALS OF ONCOLOGY Barata, P. C., Koshkin, V. S., Funchain, P., Sohal, D., Pritchard, A., Klek, S., Adamowicz, T., Gopalakrishnan, D., Garcia, J., Rini, B., Grivas, P. 2017; 28 (10): 2458-2463

  Abstract

  Advances in cancer genome sequencing have led to the development of various next-generation sequencing (NGS) platforms. There is paucity of data regarding concordance of different NGS tests carried out in the same patient.Here, we report a pilot analysis of 22 patients with metastatic urinary tract cancer and available NGS data from paired tumor tissue [FoundationOne (F1)] and cell-free circulating tumor DNA (ctDNA) [Guardant360 (G360)].The median time between the diagnosis of stage IV disease and the first genomic test was 23.5 days (0-767), after a median number of 0 (0-3) prior systemic lines of treatment of advanced disease. Most frequent genomic alterations (GA) were found in the genes TP53 (50.0%), TERT promoter (36.3%); ARID1 (29.5%); FGFR2/3 (20.5%), PIK3CA (20.5%) and ERBB2 (18.2%). While we identified GA in both tests, the overall concordance between the two platforms was only 16.4% (0%-50%), and 17.1% (0%-50%) for those patients (n = 6) with both tests conducted around the same time (median difference = 36 days). On the contrary, in the subgroup of patients (n = 5) with repeated NGS in ctDNA after a median of 1 systemic therapy between the two tests, average concordance was 55.5% (12.1%-100.0%). Tumor tissue mutational burden was significantly associated with number of GA in G360 report (P < 0.001), number of known GA (P = 0.009) and number of variants of unknown significance (VUS) in F1 report (P < 0.001), and with total number of GA (non-VUS and VUS) in F1 report (P < 0.001).This study suggests a significant discordance between clinically available NGS panels in advanced urothelial cancer, even when collected around the same time. There is a need for better understanding of these two possibly complementary NGS platforms for better integration into clinical practice.

  View details for DOI 10.1093/annonc/mdx405

  View details for Web of Science ID 000411827200020

  View details for PubMedID 28945843

• Changing Treatment Paradigms for Brain Metastases From Melanoma PART 2: When and How to Use the N.ew Systemk Agents ONCOLOGY-NEW YORK Venur, V., Funchain, P., Kotecha, R., Chao, S. T., Ahluwalia, M. S. 2017; 31 (9): 659-667

  Abstract

  Until recently, therapeutic strategies for melanoma brain metastases focused on local treatments: surgery, whole-brain radiation therapy, and stereotactic radiosurgery. Historically, systemic therapy had limited utility. Immunotherapeutic drugs, such as anti-cytotoxic T-lymphocyte-associated antigen 4 and anti-programmed death 1 agents, and agents targeting the BRAF-MEK pathway have revolutionized the systemic treatment of melanoma brain metastases. Recent clinical trials of these agents have shown activity against melanoma brain metastases, and they are increasingly being used in clinical practice. In this article, we provide an overview of the currently available systemic agents, including immunotherapeutic agents and targeted tyrosine kinase inhibitors. We also provide a practical management algorithm to guide the practicing oncologist in the use of both of these new therapies and the more traditional local treatments.

  View details for Web of Science ID 000411660100002

  View details for PubMedID 29071693

• Changing Treatment Paradigms for Brain Metastases From Melanoma ONCOLOGY-NEW YORK Venur, V., Funchain, P., Kotecha, R., Chao, S. T., Ahluwalia, M. S. 2017; 31 (8): 602-606

  Abstract

  Melanoma is the third most common cause of brain metastases, after lung and breast cancer. The management of melanoma brain metastases can be broadly divided into symptom control and therapeutic strategies. Supportive treatments include corticosteroids to reduce peritumoral edema, antiepileptics for seizure control, and medications to preserve cognitive function. Until recently, therapeutic strategies consisted primarily of local treatments, including surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). Surgery, WBRT, and SRS-alone and in various combinations-still play an important role in treatment, especially in patients with few and/or smaller brain lesions. Much work has been done recently to try to determine the optimal settings for these therapies, the most effective ways to combine them, and ideal radiation dose and fractions.

  View details for Web of Science ID 000408403500002

  View details for PubMedID 28812301

• Metabolomic analysis identifies differentially produced oral metabolites, including the oncometabolite 2-hydroxyglutarate, in patients with head and neck squamous cell carcinoma. BBA clinical Mukherjee, P. K., Funchain, P., Retuerto, M., Jurevic, R. J., Fowler, N., Burkey, B., Eng, C., Ghannoum, M. A. 2017; 7: 8-15

  Abstract

  Metabolomics represents a promising approach for discovering novel targets and biomarkers in head and neck squamous cell carcinoma (HNSCC). Here we used metabolomics to identify oral metabolites associated with HNSCC.Tumor and adjacent normal tissue from surgical resections and presurgical oral washes as well as oral washes were collected from healthy participants. Metabolites extractions of these samples were analyzed by liquid chromatography-mass spectroscopy (LC/MS), LC/MS/MS and gas chromatography-MS (GC/MS).Among 28 samples obtained from 7 HNSCC cases and 7 controls, 422 metabolites were detected (269 identified and 153 unidentified). Oral washes contained 12 and 23 metabolites in healthy controls and HNSCC patients, respectively, with phosphate and lactate being the most abundant. Small molecules related to energy metabolism were significantly elevated in HNSCC patients compared to controls. Levels of beta-alanine, alpha-hydroxyisovalerate, tryptophan, and hexanoylcarnitine were elevated in HNSCC oral washes compared to healthy controls (range 7.8-12.2-fold). Resection tissues contained 22 metabolites, of which eight were overproduced in tumor by 1.9- to 12-fold compared to controls. TCA cycle analogs 2-hydroxyglutarate (2-HG) and 3-GMP were detected exclusively in tumor tissues. Targeted quantification of 2-HG in a representative HNSCC patient showed increase in tumor tissue (14.7 μg/mL), but undetectable in normal tissue. Moreover, high levels of 2-HG were detected in HNSCC cell lines but not in healthy primary oral keratinocyte cultures.Oral metabolites related to energy metabolism were elevated in HNSCC, and acylcarnitine and 2HG may have potential as non-invasive biomarkers. Further validation in clinical studies is warranted.

  View details for DOI 10.1016/j.bbacli.2016.12.001

  View details for PubMedID 28053877

  View details for PubMedCentralID PMC5199158

• Precision oncology experience at a tertiary care center. Sadaps, M., Funchain, P., Grivas, P., Estfan, B. N., Abraham, J., Stevenson, J., Pennell, N. A., Khorana, A. A., Bolwell, B., Sohal, D. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.e18118

  View details for Web of Science ID 000411931707028

• Single-center experience of PD1 inhibition in metastatic uveal melanoma. Xu, T., Song, J., McNamara, M. J., Gastman, B., Singh, A. D., Funchain, P. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.7_suppl.87

  View details for Web of Science ID 000443282900084

• Flow cytometric detection of MDSC populations in unfractionated blood. Diaz-Montero, C., Rayman, P. A., Kim, J., Pavicic, P. G., Tannenbaum, C., Velcheti, V., Funchain, P., Ko, J. S., Grivas, P., Rini, B. I., Montero, A. J., Finke, J. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.7_suppl.56

  View details for Web of Science ID 000443282900054

• Do patients learn from survivorship care plans? Bodmann, J., Harr, B., Rybicki, L. A., Koyfman, S. A., Geiger, J., Funchain, P., Joshi, N., Woody, N., Ives, D. I., Hamker, J. F., Adelstein, D. J. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.5_suppl.73

  View details for Web of Science ID 000443300500068

• Microbiomic differences in tumor and paired-normal tissue in head and neck squamous cell carcinomas. Genome medicine Wang, H., Funchain, P., Bebek, G., Altemus, J., Zhang, H., Niazi, F., Peterson, C., Lee, W. T., Burkey, B. B., Eng, C. 2017; 9 (1): 14

  Abstract

  While the role of the gut microbiome in inflammation and colorectal cancers has received much recent attention, there are few data to support an association between the oral microbiome and head and neck squamous cell carcinomas. Prior investigations have been limited to comparisons of microbiota obtained from surface swabs of the oral cavity. This study aims to identify microbiomic differences in paired tumor and non-tumor tissue samples in a large group of 121 patients with head and neck squamous cell carcinomas and correlate these differences with clinical-pathologic features.Total DNA was extracted from paired normal and tumor resection specimens from 169 patients; 242 samples from 121 patients were included in the final analysis. Microbiomic content of each sample was determined using 16S rDNA amplicon sequencing. Bioinformatic analysis was performed using QIIME algorithms. F-testing on cluster strength, Wilcoxon signed-rank testing on differential relative abundances of paired tumor-normal samples, and Wilcoxon rank-sum testing on the association of T-stage with relative abundances were conducted in R.We observed no significant difference in measures of alpha diversity between tumor and normal tissue (Shannon index: p = 0.13, phylogenetic diversity: p = 0.42). Similarly, although we observed statistically significantly differences in both weighted (p = 0.01) and unweighted (p = 0.04) Unifrac distances between tissue types, the tumor/normal grouping explained only a small proportion of the overall variation in the samples (weighted R2 = 0.01, unweighted R2 < 0.01). Notably, however, when comparing the relative abundances of individual taxa between matched pairs of tumor and normal tissue, we observed that Actinomyces and its parent taxa up to the phylum level were significantly depleted in tumor relative to normal tissue (q < 0.01), while Parvimonas was increased in tumor relative to normal tissue (q = 0.01). These differences were more pronounced among patients with more extensive disease as measured by higher T-stage.Matched pairs analysis of individual tumor-normal pairs revealed significant differences in relative abundance of specific taxa, namely in the genus Actinomyces. These differences were more pronounced among patients with higher T-stage. Our observations suggest further experiments to interrogate potential novel mechanisms relevant to carcinogenesis associated with alterations of the oral microbiome that may have consequences for the human host.

  View details for DOI 10.1186/s13073-017-0405-5

  View details for PubMedID 28173873

  View details for PubMedCentralID PMC5297129

• Prevalence of HPV Infection in Racial-Ethnic Subgroups of Head and Neck Cancer Patients. Carcinogenesis Ragin, C., Liu, J. C., Jones, G., Shoyele, O., Sowunmi, B., Kennett, R., Groen, H. J., Gibbs, D., Blackman, E., Esan, M., Brandwein, M. S., Devarajan, K., Bussu, F., Chernock, R., Chien, C. Y., Cohen, M. A., Samir, E. M., Mikio, S., D'Souza, G., Funchain, P., Eng, C., Gollin, S. M., Hong, A., Jung, Y. S., Krüger, M., Lewis, J., Morbini, P., Landolfo, S., Rittà, M., Straetmans, J., Szarka, K., Tachezy, R., Worden, F. P., Nelson, D., Gathere, S., Taioli, E. 2017; 38 (2): 218-229

  Abstract

  The landscape of HPV infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3,129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P<0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16/18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P<0.0001). There was no statistically significant difference in HPV16/18 prevalence in non-oropharyngeal cancer by race (P=0.682). With regard to the pattern of HPV16/18 status and p16 expression, White patients had the highest proportion of HPV16/18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0% and 22.6%, respectively) [P <0.0001]. Our findings suggest that the pattern of HPV16/18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities.

  View details for DOI 10.1093/carcin/bgw203

  View details for PubMedID 28025390

  View details for PubMedCentralID PMC7191086

• Strategies for clinical implementation of screening for hereditary cancer syndromes. Seminars in oncology Heald, B., Marquard, J., Funchain, P. 2016; 43 (5): 609-614

  Abstract

  Hereditary cancer syndromes generally account for 5%-10% of malignancies. While these syndromes are rare, affected patients carry significantly elevated risks of developing cancer, as do their at-risk relatives. Identification of these patients is critical to ensure timely and appropriate genetic testing relevant to cancer patients and their relatives. Several guidelines and tools are available to assist clinicians. Patients suspected to have hereditary cancer syndromes should be offered genetic testing in the setting of genetic counseling by a qualified genetics professional. Germline testing ranges from testing for a known specific familial mutation to testing of a broad differential diagnosis using a pan-cancer multi-gene panel. Taking a family history, referring specific types of tumors with higher likelihood of heredity, implementing universal screening protocols such as microsatellite instability/immunohistochemistry (MSI/IHC) for specific tumors, and referring patients with somatic tumor testing that have potentially germline consequences are all important components to the identification of hereditary cancer syndromes in the oncology clinic.

  View details for DOI 10.1053/j.seminoncol.2016.08.008

  View details for PubMedID 27899194

• Clinical predictive factors of overall survival and locoregional failure in advanced laryngeal cancer treated with definitive chemoradiation. Khan, A. M., Ward, M. C., Adelstein, D. J., Koyfman, S. A., Reddy, C. A., Bhateja, P., Funchain, P., Lamarre, E., Burkey, B., Khan, M., Scharpf, J., Prendes, B., Greskovich, J., Lorenz, R., Joshi, N., Rahe, M. L., Ives, D. I., Harr, B., Bodmann, J., Nwizu, T. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.6037

  View details for Web of Science ID 000404711502164

• Clinical Predictors of Locoregional Failure in Advanced Laryngeal Cancer Treated With Definitive Chemotherapy and Radiation Khan, A. M., Ward, M. C., Adelstein, D. J., Koyfman, S., Reddy, C. A., Bhateja, P., Funchain, P., Lamarre, E., Burkey, B. B., Khan, M., Scharpf, J., Prendes, B., Greskovich, J. F., Lorenz, R., Joshi, N. P., Rahe, M., Ives, D., Harr, B., Bodmann, J., Nwizu, T. ELSEVIER SCIENCE INC. 2016: 902

  View details for DOI 10.1016/j.ijrobp.2015.12.113

  View details for Web of Science ID 000371581900119

• Complete Durable Response From Carboplatin and Olaparib in a Heavily Pretreated Triple-Negative Metastatic Breast Cancer With Germline BRCA2 and "BRCAness" Mutations. Journal of oncology practice Hong, S., Funchain, P., Haddad, A., Crowe, J., Dalpiaz, N., Abraham, J. 2016; 12 (3): 270-2

  View details for DOI 10.1200/JOP.2016.010710

  View details for PubMedID 26962171

• Prospective Clinical Study of Precision Oncology in Solid Tumors. Journal of the National Cancer Institute Sohal, D. P., Rini, B. I., Khorana, A. A., Dreicer, R., Abraham, J., Procop, G. W., Saunthararajah, Y., Pennell, N. A., Stevenson, J. P., Pelley, R., Estfan, B., Shepard, D., Funchain, P., Elson, P., Adelstein, D. J., Bolwell, B. J. 2015; 108 (3)

  Abstract

  Systematic studies evaluating clinical benefit of tumor genomic profiling are lacking. We conducted a prospective study in 250 patients with select solid tumors at the Cleveland Clinic. Eligibility required histopathologic diagnosis, age of 18 years or older, Eastern Cooperative Oncology Group performance status 0-2, and written informed consent. Tumors were sequenced using FoundationOne (Cambridge, MA). Results were reviewed at the Cleveland Clinic Genomics Tumor Board. Outcomes included feasibility and clinical impact. Colorectal (25%), breast (18%), lung (13%), and pancreatobiliary (13%) cancers were the most common diagnoses. Median time from consent to result was 25 days (range = 3-140). Of 223 evaluable samples, 49% (n = 109) of patients were recommended a specific therapy, but only 11% (n = 24) received such therapy: 12 on clinical trials, nine off-label, three on-label. Lack of clinical trial access (n = 49) and clinical deterioration (n = 29) were the most common reasons for nonrecommendation/nonreceipt of genomics-driven therapy.

  View details for DOI 10.1093/jnci/djv332

  View details for PubMedID 26553780

• Comprehensive Functional Genomic Profiling of HPV Unassociated Head and Neck Squamous Cell Cancer Identifies Neomorphic Mutations That Confer Resistance to Therapy Kittel, J., Funchain, P., Chute, D., Woody, N. M., Hammerman, P., Koyfman, S., Abazeed, M. ELSEVIER SCIENCE INC. 2015: E538

  View details for DOI 10.1016/j.ijrobp.2015.07.1925

  View details for Web of Science ID 000373215301416

• Prospective clinical study of precision oncology in solid tumors Sohal, D., Rini, B. I., Khorana, A. A., Dreicer, R., Abraham, J., Procop, G., Saunthararajah, Y., Pennell, N. A., Stevenson, J., Pelley, R., Estfan, B. N., Shepard, D., Funchain, P., Adelstein, D. J., Bolwell, B. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for DOI 10.1200/jco.2015.33.15_suppl.6585

  View details for Web of Science ID 000358036901499

• Hereditary implications of somatic tumor testing Funchain, P., Sohal, D., Khorana, A. A., Abraham, J., Pennell, N. A., Rini, B. I., Dreicer, R., Bolwell, B., Eng, C. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for DOI 10.1200/jco.2015.33.15_suppl.1523

  View details for Web of Science ID 000358036900390

• Microbiomes of Inflammatory and Non-Inflammatory Thoracic Aortic Aneurysms. Funchain, P., Hoffman, G. S., Svensson, L., Roselli, E., Pettersson, G., Johnston, D., Soltesz, E., Chakravarti, R., Clifford, A., Eng, C. WILEY-BLACKWELL. 2014: S37

  View details for Web of Science ID 000344384900089

• Temporal Artery Microbiome in Giant Cell Arteritis. Clifford, A., Funchain, P., Lystad, L., Peterson, C., Altemus, J., Hoffman, G. S., Eng, C. WILEY-BLACKWELL. 2014: S343

  View details for Web of Science ID 000344384901326

• Hunting for cancer in the microbial jungle. Genome medicine Funchain, P., Eng, C. 2013; 5 (5): 42

  View details for DOI 10.1186/gm446

  View details for PubMedID 23731547

  View details for PubMedCentralID PMC3707053

• Correlation of microbiomic profiles with disease status and <i>MDR1</i> methylation in head and neck squamous cell carcinoma (HNSCC). Funchain, P., Bebek, G., Bennett, K. L., Burkey, B., Eng, C. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009800180

• Microbiomic subprofiles and MDR1 promoter methylation in head and neck squamous cell carcinoma Bebek, G., Bennett, K. L., Funchain, P., Campbell, R., Seth, R., Scharpf, J., Burkey, B., Eng, C. AMER ASSOC CANCER RESEARCH. 2012

  View details for DOI 10.1158/1538-7445.AM2012-4087

  View details for Web of Science ID 000209701605475

• A reinvestigation of somatic hypermethylation at the <i>PTEN</i> CpG island in cancer cell lines BIOLOGICAL PROCEDURES ONLINE Hesson, L. B., Packham, D., Pontzer, E., Funchain, P., Eng, C., Ward, R. L. 2012; 14: 5

  Abstract

  PTEN is an important tumour suppressor gene that is mutated in Cowden syndrome as well as various sporadic cancers. CpG island hypermethylation is another route to tumour suppressor gene inactivation, however, the literature regarding PTEN hypermethylation in cancer is controversial. Furthermore, investigation of the methylation status of the PTEN CpG island is challenging due to sequence homology with the PTEN pseudogene, PTENP1. PTEN shares a CpG island promoter with another gene known as KLLN. Here we present a thorough reinvestigation of the methylation status of the PTEN CpG island in DNA from colorectal, breast, ovarian, glioma, lung and haematological cancer cell lines.Using a range of bisulphite-based PCR assays we investigated 6 regions across the PTEN CpG island. We found that regions 1-4 were not methylated in cancer cell lines (0/36). By allelic bisulphite sequencing and pyrosequencing methylation was detected in regions 5 and 6 in colorectal, breast and haematological cancer cell lines. However, methylation detected in this region was associated with the PTENP1 promoter and not the PTEN CpG island.We show that methylation of the PTEN CpG island is a rare event in cancer cell lines and that apparent methylation most likely originates from homologous regions of the PTENP1 pseudogene promoter. Future studies should utilize assays that reliably discriminate between PTEN and PTENP1 to avoid data misinterpretation.

  View details for DOI 10.1186/1480-9222-14-5

  View details for Web of Science ID 000307213500001

  View details for PubMedID 22490388

  View details for PubMedCentralID PMC3342897

• Microbiomic subprofiles and <i>MDR1</i> promoter methylation in head and neck squamous cell carcinoma HUMAN MOLECULAR GENETICS Bebek, G., Bennett, K. L., Funchain, P., Campbell, R., Seth, R., Scharpf, J., Burkey, B., Eng, C. 2012; 21 (7): 1557-1565

  Abstract

  Clinical observations and epidemiologic studies suggest that the incidence of head and neck squamous cell carcinoma (HNSCC) correlates with dental hygiene, implying a role for bacteria-induced inflammation in its pathogenesis. Here we begin to explore the pilot hypothesis that specific microbial populations may contribute to HNSCC pathogenesis via epigenetic modifications in inflammatory- and HNSCC-associated genes. Microbiomic profiling by 16S rRNA sequencing of matched tumor and adjacent normal tissue specimens in 42 individuals with HNSCC demonstrate a significant association of specific bacterial subpopulations with HNSCC over normal tissue (P < 0.01). Furthermore, microbial populations can separate tumors by tobacco status (P < 0.008), but not by alcohol status (P = 0.41). If our subhypothesis regarding a mechanistic link from microorganism to carcinogenesis via inflammation and consequent aberrant DNA methylation is correct, then we should see hypermethylation of relevant genes associate with specific microbiomic profiles. Methylation analysis in four genes (MDR1, IL8, RARB, TGFBR2) previously linked to HNSCC or inflammation shows significantly increased methylation in tumor samples compared with normal oral mucosa. Of these, MDR1 promoter methylation associates with specific microbiomic profiles in tumor over normal mucosa. Additionally, we report that MDR1 methylation correlates with regional nodal metastases in the context of two specific bacterial subpopulations, Enterobacteriaceae and Tenericutes (P < 0.001 for each). These associations may lead to a different, and potentially more comprehensive, perspective on the pathogenesis of HNSCC, and support further exploration of mechanistic linkage and, if so, novel therapeutic strategies such as demethylating agents and probiotic adjuncts, particularly for patients with advanced or refractory disease.

  View details for DOI 10.1093/hmg/ddr593

  View details for Web of Science ID 000301299700010

  View details for PubMedID 22180460

  View details for PubMedCentralID PMC3298279

• Acute liver injury induced by weight-loss herbal supplements WORLD JOURNAL OF HEPATOLOGY Chen, G. C., Ramanathan, V. S., Law, D., Funchain, P., Chen, G. C., French, S., Shlopov, B., Eysselein, V., Chung, D., Reicher, S., Pham, B. 2010; 2 (11): 410-415

  Abstract

  We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss.

  View details for DOI 10.4254/wjh.v2.i11.410

  View details for Web of Science ID 000439123200004

  View details for PubMedID 21173910

  View details for PubMedCentralID PMC3004035

• Mutants with temperature-sensitive defects in the <i>Escherichia coli</i> mismatch repair system:: Sensitivity to mispairs generated in vivo JOURNAL OF BACTERIOLOGY Hong, E. S., Yeung, A., Funchain, P., Slupska, M. M., Miller, J. H. 2005; 187 (3): 840-846

  Abstract

  We have used direct selections to generate large numbers of mutants of Escherichia coli defective in the mismatch repair system and have screened these to identify mutants with temperature-sensitive defects. We detected and sequenced mutations that give rise to temperature-sensitive MutS, MutL, and MutH proteins. One mutation, mutS60, results in almost normal levels of spontaneous mutations at 37 degrees C but above this temperature gives rise to higher and higher levels of mutations, reaching the level of null mutations in mutS at 43 degrees C. However, at 37 degrees C the MutS60 protein can be much more easily titrated by mispairs than the wild-type MutS, as evidenced by the impaired ability to block homologous recombination in interspecies crosses and the increased levels of mutations from weak mutator alleles of mutD (dnaQ), mutC, and ndk. Strains with mutS60 can detect mispairs generated during replication that lead to mutation with much greater sensitivity than wild-type strains. The findings with ndk, lacking nucleotide diphosphate kinase, are striking. An ndk mutS60 strain yields four to five times the level of mutations seen in a full knockout of mutS. These results pose the question of whether similar altered Msh2 proteins result from presumed polymorphisms detected in tumor lines. The role of allele interactions in human disease susceptibility is discussed.

  View details for DOI 10.1128/JB.187.3.840-846.2005

  View details for Web of Science ID 000226705200004

  View details for PubMedID 15659661

  View details for PubMedCentralID PMC545721

• Epigenetic profiling in chronic lymphocytic leukemia reveals novel methylation targets CANCER RESEARCH Rush, L. J., Raval, A., Funchain, P., Johnson, A. J., Smith, L., Lucas, D. M., Bembea, M., Liu, T. H., Heerema, N. A., Rassenti, L., Liyanarachchi, S., Davuluri, R., Byrd, J. C., Plass, C. 2004; 64 (7): 2424-2433

  Abstract

  CpG island methylation is an epigenetic alteration that contributes to tumorigenesis by transcriptional inactivation of genes. Little is known about the overall levels of CpG island methylation in chronic lymphocytic leukemia (CLL). To provide a baseline estimate of global aberrant methylation and identify target sequences for additional investigation, we performed Restriction Landmark Genomic Scanning on 10 CLL samples. Two methylation-sensitive landmark enzymes were used (NotI and AscI), allowing assessment of over 3000 CpG islands in each sample. Tumor-derived Restriction Landmark Genomic Scanning profiles were compared with profiles from CD19-selected B cells from normal volunteers and matched normal neutrophils from 4 CLL patients. We found 2.5-8.1% (mean 4.8%) of the CpG islands in CLL samples were aberrantly methylated compared with controls, and the methylation events had a nonrandom distribution (P < 0.0001). Furthermore, we identified 193 aberrantly methylated sequences, of which 93% have CpG island characteristics and 90% have homology to genes or expressed sequences. One such gene, the G protein-coupled metabotropic glutamate receptor 7 (GRM7), possibly inhibits cyclic AMP signaling in the induction of apoptosis. Bisulfite sequencing of GRM7 confirmed extensive CpG island methylation, and treatment with 5-aza-2'-deoxycytidine (decitabine) resulted in up-regulated expression of several genes in vitro with concurrent cellular depletion of DNMT1 protein. Our dual-enzyme global methylation study shows that CLL is characterized by widespread nonrandom CpG island methylation similar to other tumors and provides a panel of novel methylation targets that can be used in larger studies designed to assess impact on disease progression and survival.

  View details for DOI 10.1158/0008-5472.CAN-03-2870

  View details for Web of Science ID 000220586500019

  View details for PubMedID 15059895

• In vitro and in vivo studies of MutS, MutL and MutH mutants: correlation of mismatch repair and DNA recombination DNA REPAIR Junop, M. S., Yang, W., Funchain, P., Clendenin, W., Miller, J. H. 2003; 2 (4): 387-405

  Abstract

  We have used the recently determined crystal structures of Escherichia coli (E. coli) MutS, MutL and MutH to guide construction of 47 amino-acid substitutions in these proteins and analyzed their behavior in mismatch repair and recombination in vitro and in vivo. We find that the active site of the MutH endonuclease is composed of regions from two separate structural domains and that the C-terminal 5 residues of MutH influence both DNA binding and cleavage. We also find that the non-specific DNA-binding activity of MutL is required for mismatch repair and probably functions after strand cleavage by MutH. Alteration of residues in either the mismatch recognition domain, the ATPase active site, or the domain interfaces linking the two activities can diminish the differential binding of MutS to homoduplex versus heteroduplex and results in the loss of mismatch-specific MutH activation. Finally, every mutation that abolishes mismatch repair is deficient in blocking homeologous recombination, suggesting that mismatch repair and prevention of homeologous recombination use the same MutS-MutL complexes for signaling in E. coli.

  View details for DOI 10.1016/S1568-7864(02)00245-8

  View details for Web of Science ID 000181649000003

  View details for PubMedID 12606120

• Aberrant DNA methylation in chronic lymphocytic leukemia: A role in pathogenesis? Raval, A., Rush, L. J., Funchain, P., Flak, E., Davis, M., Johnson, A. J., Byrd, J. C., Plass, C. AMER SOC HEMATOLOGY. 2002: 379A

  View details for Web of Science ID 000179184701470

• <i>Escherichia coli</i> strains (<i>ndk</i>) lacking nudeoside diphosphate kinase are powerful mutators for base substitutions and frameshifts in mismatch-repair-deficient strains GENETICS Miller, J. H., Funchain, P., Clendenin, W., Huang, T., Nguyen, A., Wolff, E., Yeung, A., Chiang, J. H., Garibyan, L., Slupska, M. M., Yang, H. J. 2002; 162 (1): 5-13

  Abstract

  Nucleoside diphosphate (NDP) kinase is one of the enzymes that maintains triphosphate pools. Escherichia coli strains (ndk) lacking this enzyme have been shown to be modest base substitution mutators, and two members of the human family of NDP kinases act as tumor suppressors. We show here that in E. coli strains lacking NDP kinase high levels of mispairs are generated, but most of these are corrected by the mismatch-repair system. Double mutants that are ndk mutS, lacking both the NDP kinase and mismatch repair, have levels of base substitutions 15-fold higher and levels of certain frameshifts up to 10-fold higher than those of the respective mutations in mutS strains that are NDP kinase proficient. A sequence analysis of the specificity of base substitution mutations generated in ndk and ndk mutS backgrounds as well as other experiments suggests that NDP kinase deficiency stimulates polymerase errors that lead to A:T --> G:C transitions and that the editing capacity of cells may be affected, leading to additional uncorrected mispairs and to A:T --> T:A transversions.

  View details for Web of Science ID 000178363400002

  View details for PubMedID 12242219

  View details for PubMedCentralID PMC1462255

• Amplification of mutator cells in a population as a result of horizontal transfer JOURNAL OF BACTERIOLOGY Funchain, P., Yeung, A., Stewart, J., Clendenin, W. M., Miller, J. H. 2001; 183 (12): 3737-3741

  Abstract

  Mutator cells that lack the mismatch repair system (MMR(-)) occur at rates of 10(-5) or less in laboratory populations started from wild-type cells. We show that after selection for recombinants in an interspecies mating between Salmonella enterica serovar Typhimurium and Escherichia coli, the percentage of MMR(-) cells rises to several percent of the recombinant population, and after a second successive mating and selection, greater than 95% of the recombinants are MMR(-). Coupling a single cross and selection with either mutagenesis or selection for spontaneous mutants also results in a dramatic increase in MMR(-) cells. We discuss how horizontal transfer can result in mutator strains during adaptive evolution.

  View details for DOI 10.1128/JB.183.12.3737-3741.2001

  View details for Web of Science ID 000168990400023

  View details for PubMedID 11371538

  View details for PubMedCentralID PMC95251

• The consequences of growth of a mutator strain of <i>Escherichia coli</i> as measured by loss of function among multiple gene targets and loss of fitness GENETICS Funchain, P., Yeung, A., Stewart, J. L., Lin, R., Slupska, M. M., Miller, J. H. 2000; 154 (3): 959-970

  Abstract

  We have examined the composition of members of mutator populations of Escherichia coli by employing an extensive set of phenotypic screens that allow us to monitor the function of >700 genes, constituting approximately 15% of the genome. We looked at mismatch repair deficient cells after repeated cycles of single colony isolation on rich medium to generate lineages that are forced through severe bottlenecks, and compared the results to those for wild-type strains. The mutator lineages continued to accumulate mutations rapidly with each increasing cycle of colony isolation. By the end of the 40th cycle, after approximately 1000 generations, most of the lineages had reduced colony size, 4% had died out, 55% had auxotrophic requirements (increasing to 80% after 60 cycles), and 70% had defects in at least one sugar or catabolic pathway. In addition, 33% had a defect in cell motility, and 26% were either temperature-sensitive or cold-sensitive lethals. On the other hand, only 3% of the wild-type lineages had detectable mutations of any type after 40 cycles. By the 60th cycle, the typical mutator cell carried 4-5 inactive genes among the 15% of the genome being monitored, indicating that the average cell carried at least 24-30 inactivated genes distributed throughout the genome. Remarkably, 30% of the lineages had lost the ability to utilize xylose as a carbon source. DNA sequencing revealed that most of the Xyl(-) mutants had a frameshift in a run of eight G's (GGGGGGGG) in the xylB gene, either adding or deleting one -G-. Further analysis indicated that rendering E. coli deficient in mismatch repair unmasks hypermutable sites in certain genes or intergenic regions. Growth curves and competition tests on lineages that passed through 90 cycles of single colony isolation showed that all lineages suffered reduced fitness. We discuss these results in terms of the value of mutators in cellular evolution.

  View details for Web of Science ID 000085720500003

  View details for PubMedID 10757746

  View details for PubMedCentralID PMC1461004

• Temporary and Permanent,Mutators lacking the mismatch repair system: The enhancement of mutators in cell populations Miller, J. H., Yeung, A., Funchain, P., Mao, E., Stewart, J., Clendenin, W. M., Slupska, M. M. COLD SPRING HARBOR LAB PRESS. 2000: 241-252

  View details for DOI 10.1101/sqb.2000.65.241

  View details for Web of Science ID 000169676800025

  View details for PubMedID 12760038